Can the Research on the Acute Phase Response that Comes from the Critical Care Nutrition Community Be Applied to Chronic Illness?
I would guess that you may have noticed that the research discussed in the last three newsletters was, for the most part, written by critical care nutritionists who were, most directly, discussing metabolic changes that occur as the result of major, acute care situations such as trauma, massive infection, burns, surgery, etc. In turn, as I hope I made abundantly clear, it is my opinion that these metabolic changes seen in critical care are also a hallmark finding with every chronic illness, no matter what the symptoms, laboratory and/or clinical presentation. In addition, I hope I made it very clear that it is my opinion that initially addressing the version of the acute phase response (APR) that almost invariably occurs in chronically ill patients can very often translate into a very cost and time effective, highly efficacious way of gaining clinical improvement, even in very complicated chronic illness presentations, which we at Moss Nutrition have termed Entry Level Clinical NutritionTM. In this installment of this series I would like to present a discussion of several papers that I feel strongly support my hypothesis that the APR that has been traditionally associated solely with acute, hospital-based situations, in reality, plays an integral role in creating the clinical picture very often seen in the chronically ill patients that make up a major portion of our practices.
AN OVERVIEW OF PAPERS THAT SUPPORT THE APR/CHRONIC ILLNESS CONNECTION
In part I of this series I provided some preliminary documentation of my hypothesis about the APR/chronic illness connection in the form of a quote from the first major paper that I know of that highlighted the similarities between acute and chronic illness, “Acute and ‘chronic’ phase reaction – a mother of disease” by Bengmark (1). Now I would like to explore this paper in much more detail so as to further document my hypothesis that the acute phase response plays an integral role in creating the signs and symptoms that we most often encounter and attempt to alleviate in the chronically ill patients who typically populate our practices.
To begin this paper, Bengmark (1) presents an overview of the acute phase response that is consistent with the descriptions I have provided from other papers:
“A series of complex reactions occur in the body when an individual is threatened by stress, mental or physical; infection, trauma, surgical operation, advanced medical treatment or child delivery-all aimed to provide optimal protection against progress of disease. These changes are usually summarized under the name of acute phase reaction (APR). These changes involve the whole body…”
Next, consider the following quote that I presented in part I of this series that highlights the important comparisons between the acute and chronic illness situations, focusing both on the similarities and differences:
“Similar, but not identical, defensive mechanisms are activated when an individual is affected by a long-lasting, continuous but discretely wearing mental and/or physical stress. The observed mechanisms have similarities with APR but also important differences. There are good reasons to keep them apart by defining the later as chronic phase response (CPR). Characteristic to APR is increase in temperature, chills, somnolence, anorexia and profound changes in blood levels of plasma proteins, lipids, minerals, hormones, cytokines as well as cellular elements. CPR manifests itself mainly as chronic fatigue, asthenia, reduced appetite, reduced physical activity, reduced mood, sometimes mental depression and in reduced muscle mass. The changes in chemical and cellular parameters in CPR, although obvious, are more discrete.”
In the next quote, Bengmark (1) elaborates on the similarities between the APR and the CPR, most of which have been discussed earlier in this series:
“Common to both the APR and CPR is hypermetabolism, increased hepatic glycogenesis, increased glucose turnover, reduced muscle uptake of glucose, hyperlipidemia and increased lipolysis of adipose tissues, especially visceral fats, increased production of non-esterified fatty acids (NEFAs), increased protein synthesis in the liver and increased protein turnover in the body, increased blood glucose levels, increased insulin secretion and insulin resistance. Fibrinogen and PAI-1 are significantly elevated in CPR, and significantly impaired fibrinolysis. Typical for CPR is increased levels of pro-oxidants such as homocysteine, and low levels of antioxidants such as folic acid and glutathione.”
Finally, consider the following quote that points out compelling similarities between the APR and CPR:
“An exaggerated CPR occurs in patients with prestage of chronic disease observed during months, sometimes years, and sometimes long before obvious signs of manifest disease. Cytokines such as IL-6 and TNF-α are early significantly elevated, so are also acute phase proteins such as C-reactive protein (CRP), fibrinogen and PAI-1, changes which signal a state of increased inflammation and increased coagulation in the body, and associated with increased deposits of fibrin on endothelial (blood vessels) and mesothelial (body cavities), and also with increased incidence of thrombosis. High levels of insulin, blood glucose, and NEFA are commonly observed.”
Before continuing, I would like to emphasize two key points from the above quotes that I feel, even though I have focused on them before, deserve still more elaboration. First, please note that increased protein production occurs in the liver which, at first glance, might be considered to be advantageous in terms of addressing the needs of chronically ill patients. Unfortunately, as I have mentioned repeatedly, this production mainly occurs in the form of pro-inflammatory, acute phase proteins such as CRP, not in the form of proteins we might consider to be most desirable in these situations such as phase I and II detoxification enzymes and proteins involved in tissue repair. Therefore, I feel we must proceed confidently but cautiously with introducing much needed protein supplementation with patients who demonstrate significant levels of inflammation and elevations of major acute phase proteins such as CRP. Second, please notice again that the cytokine IL-6 is elevated in both the APR and CPR. As I will be pointing out, many studies have noted that elevated IL-6 is a major exacerbating metabolic factor in many chronic illnesses, which I feel provides powerful support of the hypothesis that the APR is an integral causational factor of the signs and symptoms seen in chronically ill patients.
The acute phase response and cardiovascular disease (CVD)
The next paper I would like to discuss directly examines the APR in relation to one of the most common chronic illnesses encountered in this country, atherosclerosis. In “The acute phase response and atherosclerosis” by Lowenstein and Matsushita (2), the authors begin in the abstract by providing a concise overview of their opinion on this relationship, including the need to address it therapeutically, as I have been suggesting in the Entry Level Clinical Nutrition™ paradigm:
“The acute phase response (APR) is an acute systemic response to infection. Recent studies reveal that the APR is chronically activated in patients at risk for atherosclerosis. Diabetes, hypertension, and elevated cholesterol trigger the APR, leading to the systemic release of hundreds of effector molecules that might damage the endothelium and activate macrophages, driving the process of atherogenesis. The signaling molecules that mediate the APR are attractive candidates for anti-inflammatory therapy of patients with atherosclerosis.”
As most of you know, it is now well documented that cardiovascular disease (CVD) is primarily an inflammatory phenomenon. What is not as well known, though, is the idea that, according to the authors, the inflammatory process seen with CVD is part of the APR:
“Many of the inflammatory markers elevated in patients at risk for atherosclerosis are part of the APR. The APR is an innate systemic inflammatory response to diverse injuries, such as infection and trauma. Although the APR is a beneficial short-term response to life threatening physiological challenges, the APR can harm the host if it is chronically activated. Elevation of APR markers in patients with heart disease suggests that the APR plays a role in atherogenesis.”
As has been suggested in previous installments of this series, the APR is classically triggered by infection or trauma. In contrast, as was suggested in the abstract above, the APR in CVD is triggered by other factors. Lowenstein and Matsushita (2) state:
“Elevations in the APR markers in patients with atherosclerosis suggest that risk factors for heart disease – such as diabetes, mediators of hypertension, and LDL cholesterol – might trigger the APR.”
Furthermore, the authors point out what I have been suggesting; that contrary to classic APR theory, the APR in atherosclerosis operates at a low-grade, chronic level for years:
“Normally, the APR is activated within hours by infection and then shuts down within two to three days. However, in patients with atherosclerosis the APR appears to be chronically activated at a low level for years. For example, elevated CRP levels predict the risk of atherosclerosis more than six years into the future. Perhaps the continued presence of atherosclerotic risk factors such as hypertension play a role in the persistent activation of the APR.”
The acute phase response and rheumatoid arthritis
Does evidence exist that suggests the APR is involved in chronic illnesses other than CVD? The paper “Acute-phase reactants in infections and inflammatory diseases” by Ebersole and Cappelli (3) discusses the APR in relation to several chronic illnesses. Concerning rheumatoid arthritis (RA), the authors state the following:
“Several studies have demonstrated a correlation between elevated serum acute-phase proteins and the magnitude of joint destruction in rheumatoid arthritis.”
The acute phase response and Crohn’s disease
Concerning Crohn’s disease, the authors state the following:
“A cross-sectional study of Crohn’s disease showed acute-phase reactants (including C-reactive protein and haptoglobulin) changed in parallel with disease activity…”
The acute phase response and depression
Ebersole and Cappelli (3) state the following in relation to depression:
“…major depression may be accompanied by higher concentrations of positive and low concentrations of negative acute-phase proteins. Increased haptoglobulin is the most prominent change and is positively correlated with IL-6 production. Increased production of IL-6 and IL-1 in major depression may underlie both immune activation and the acute-phase response in this illness. Major depression in men resulted in significantly elevated levels of haptoglobulin and α1–antichymotrypsin and were correlated with the severity of the depression, suggesting that an inflammatory response occurs during depression.”
In addition, the authors reported similar findings with schizophrenic and manic patients.
The acute phase response and periodontal disease
Finally, Ebersole and Cappelli (3) consider periodontal disease, stating the following:
“…oral infections produce significant increases in systemic inflammatory responses, manifested by acute-phase cytokines and acute-phase proteins.”
The acute phase response and chronic inflammation
Of course, the above quotes refer only to specific chronic diseases. Does other evidence exist that supports the contention made by Bengmark (1) and me that the APR is involved in any situation where chronic inflammation exists, which, as we now know, includes virtually every major chronic illness we tend to see in our practices?
When the fact that IL-6 is a major inducer of the APR is taken into account, the answer to this question is most emphatically in the affirmative. This point was very well demonstrated by the paper “Interleukin-6 and chronic inflammation” by Gabay (4). As noted by the author, IL-6, which is a major inducer of the APR, is also a major determining factor in the transition from acute to chronic inflammation:
“The main switch from acute to chronic inflammation is the recruitment of monocytes to the area of inflammation. IL-6 is important to the transition between acute and chronic inflammation.”
Next, the author goes into more detail on the important relationship between IL-6, the APR, and chronic inflammation:
“At the beginning of acute inflammation, IL-6 mediates the acute phase responses. When its activity as a proinflammatory cytokine persists, acute inflammation turns into chronic inflammation that includes immune responses.”
In turn, as suggested above, IL-6 and, by extension, the APR, are involved in several chronic illnesses:
“Levels of circulating IL-6 are elevated in several inflammatory diseases including rheumatoid arthritis, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, anklyosing spondylitis, psoriasis and Crohn’s disease.”
Before leaving the subject of IL-6 and the APR, I would like to again discuss RA, but, in this instance in relationship to IL-6. In “Interleukin-6: A key mediator of systemic and local symptoms in rheumatoid arthritis” by Cronstein (5) the following is pointed out:
“The possibility that increased IL-6 levels have clinical importance in RA is supported by correlations between IL-6 concentrations and disease activity. In several studies, IL-6 levels have been found to correlate with surrogate markers of disease activity, including rheumatoid factor, erythrocyte sedimentation rate, and CRP. Correlations between IL-6 levels and clinical manifestations, including morning stiffness, number of inflamed joints, and Ritchie’s disease activity index, have also been reported.”
Given this information, I feel it is certainly safe to conclude that all of the other adverse metabolic changes associated with the APR described in this newsletter series such as abnormal stress hormones, negative protein balance related to gluconeogenesis, depletion of micronutrients, fluid/electrolyte imbalances, decreases in detoxification enzymes, and suboptimal levels of thyroid hormones are routinely occurring with most chronic illnesses. In turn, I feel that use of the therapeutic options discussed with Entry Level Clinical Nutrition™ are viable clinical alternatives to improving chief complaints in virtually all chronically ill patients no matter what the clinical presentation or disease diagnosis.
Rheumatoid arthritis and muscle wasting
As further proof of my hypothesis that elements of the acute phase response are present in virtually every chronically ill patient, I would next like to discuss a paper that makes it clear that one of the most clinically important elements of the acute phase response, muscle wasting related to hypermetabolism and excessive gluconeogenesis, is present in a large portion of patients who suffer from one of the more common chronic illnesses, rheumatoid arthritis. In the paper “Rheumatoid cachexia: a clinical perspective” by Summers et al (6), the authors state the following:
“Rheumatoid cachexia has been described and analysed in a series of studies and reviews by Roubenoff and colleagues over the past 15 years including a review in this journal in 2004. They describe evidence of cachexia in two-thirds of rheumatoid arthritis (RA) patients with muscle wasting and often compensatory increase in fat mass; the so-called cachectic obesity; with loss of weight or BMI being uncommon. They have provided evidence for a state of cytokine (primarily TNF-α)-driven hypermetabolism causing an increased level of muscle protein degradation.”
In their conclusion, Summers et al (6) discuss the relationship between RA, cachexia, and the acute phase response from a “big picture” perspective:
“RA is a chronic inflammatory autoimmune disease resulting in joint inflammation, increased risk of cardiovascular disease and osteoporosis, with high circulating levels of cytokines and acute phase proteins. This can produce a loss of muscle mass with maintenance of fat mass but ultimately leads to weight loss in the more severely affected patient. The cachectic state may give rise to a vicious cycle of decreasing exercise, increased fatigue and weakness and an increase in fat mass (rheumatoid cachectic obesity) with implications for comorbidity and mortality. However, in common with other cachectic conditions, there seems to be a direct association between survival and increasing body weight.”
Interestingly, in line with one of the foundational concepts of Entry Level Clinical Nutrition™ that multiple metabolic interventions are generally necessary to gain clinical improvement in chronically ill patients, the authors note that dietary improvements alone have either no or minimal effect. Summers et al (6) state:
“In common with other types of cachexia, there is evidence that muscle tissue exhibits ‘anabolic resistance’-a general failure of muscle protein synthesis to increase adequately in response to food. Overfeeding in patients with RA is therefore not advisable as this could induce an increase in fat mass, with possible consequences for cardiovascular and metabolic health.”
Nevertheless, the authors did report that amino acid supplementation can yield some small improvements:
Marcora et al. investigated dietary treatment of rheumatoid cachexia using a nutritional supplement of β-hydroxy-β-methyl-butyrate, glutamine and arginine, providing 7.19 g/day nitrogen and 180 kcal/day, compared with a nitrogen and calorie equivalent mixture of ‘non-essential’ amino acids (alanine, glutamic acid, glycine and serine) used as placebo. Both interventions increased muscle mass to a similar extent over a 12-week period (by 2-3%) indicating that rheumatoid cachexia may to some extent respond to nitrogen supplementation.”
Furthermore, again in line with Entry Level Clinical Nutrition™ principles, Summers et al (6) noted that combining nutritional therapy with resistance training and anti-inflammatory therapy may be the best approach to reversing RA cachexia. In their discussion of using anti-cytokine therapy, the authors point out:
“It may be that adjunctive anabolic therapy, such as progressive resistance training or nitrogen supplementation, is needed to reverse rheumatoid cachexia.”
IL-6, inflammation, and sarcopenia
As I have mentioned in previous newsletters, while muscle loss related to cachexia is a major cause of symptomatology and loss of quality of life in more severe chronic situations revolving around RA, cancer, and CVD, muscle loss related to sarcopenia is very prevalent and intimately involved in creating and exacerbating chief complaints in many chronically ill patients. Therefore, it is my opinion that the demonstration of a relationship between IL-6, inflammation, and sarcopenia would certainly provide very strong evidence that the APR plays a major role in many chronic illnesses. As you will see, the paper entitled “Inflammation: roles in aging and sarcopenia” by Jensen (7) provides strong evidence that this relationship indeed exists.
How common is sarcopenia? Even though I have discussed this issue before, I feel the sobering statistics bear repeating. Jensen (7) states:
“Muscle mass is lost at a rate of 1%-2% per year past age 50 years. Approximately one-third of women and two-thirds of men older than age 60 have sarcopenia in the United States. The direct healthcare cost of sarcopenia in the U.S. in 2000 has been estimated at $18.5 billion.”
Of course, as I have been suggesting in Entry Level Clinical Nutrition™, chronic issues such as sarcopenia have many causes. In agreement, Jensen (7) notes:
“Sarcopenia is multifactorial, with contributing factors that may include loss of α-motor neuron input, changes in anabolic hormones, decreased intake of dietary protein, and decline in physical activity.”
Nevertheless, inflammation and IL-6 activity also play a significant role:
“Elevated levels of IL-6 carry a poor prognosis in older persons, and cellular IL-6 has been a significant predictor of sarcopenia in older women. Measures of inflammation, including IL-6 and C-reactive protein (CRP), identify high-functioning older persons at greater risk for functional decline and mortality.”
With the above in mind, Jensen (7) concludes:
“The pathophysiology of sarcopenia is undoubtedly multifactorial, but research findings suggest that sarcopenia is a low-level, smoldering inflammatory state driven by cytokines and oxidative stress.”
Acute phase response and anemia of chronic disease
As you may recall from part III of this series, Kushner and Rzewnicki (8) suggested a direct correlation between the APR and chronic illness when they discussed “anemia of chronic disease” in their chapter on the APR. Raj (9) provides more information on this major connection between the APR and chronic illness. First, the author discusses the exact nature of anemia of chronic disease (ACD):
“Anemia of chronic disease (ACD) occurs in patients with acute or chronic immune activation such as infection, cancer, autoimmune disease, or chronic kidney disease. ACD is characterized by normocytic or microcytic iron-deficiency anemia, low serum iron, and preserved marrow iron. Although the underlying mechanisms of ACD are not completely understood, there is a broad consensus that pro-inflammatory cytokines have an important role in this syndrome. Accordingly, ACD is also known as ‘anemia of inflammation.”
What is the specific impact of the APR in iron metabolism? The author notes:
“During acute-phase reactions, pro-inflammatory cytokines impair iron metabolism, particularly plasma iron turnover and ferritin synthesis. As a result, patients with acute and chronic infections have lower serum iron, lower transferrin saturation, and higher ferritin concentrations than do persons without apparent inflammation.”
Of course, as you might expect by now, IL-6 plays a major role in this relationship. Raj (9) states:
“Following the IL-6 mediated production of ferritin, iron is retained in the intracellular space of the reticuloendothelial system, thereby lowering the availability of iron needed for erythrocytes. In animal studies, administration of IL-6 decreased serum iron and transferrin saturation as it induced anemia.”
Thus, I feel that the relationship between the APR, IL-6 and chronic anemia provides still more, very powerful documentation that the APR plays a major role in creating all that we see in chronically ill patients.
SOME CLOSING THOUGHTS
As I hope I have profusely demonstrated, the APR and its relationship to clinical nutrition is not just an obscure bit of nutritional trivia that can be found in dusty corners of medical libraries and the rare intensive care units that are willing to deviate from the usual “standard of care.” Rather, it not only plays an integral role in creating the many metabolic imbalances we see routinely with the majority of our chronically ill patients but, because of its uniform presentation no matter what the disease or clinical signs and symptoms, it provides a concise, straightforward, and fairly simple “road map” to initiate time and cost effective clinical improvements no matter how complicated the overall clinical presentation. In turn, it forms the foundational scientific and metabolic basis for Entry Level Clinical Nutrition™.
Of course, from the beginning, I realized that the potential scientific “weak link” in Entry Level Clinical Nutrition™ was the fact that most of the research I was using to document its validity came from severely ill, acute care patients that, at first glance, seem to have little in common with the chronically ill patients we see every day. Hopefully, what I have presented in this newsletter will satisfy any skeptics who maintain that Entry Level Clinical Nutrition™ lacks a solid research basis in terms of its application with chronic illness.
In part VII of this series, I will be exploring another body of literature that provides further documentation that the large variety of signs and symptoms seen with chronically ill patients are not caused by complex, highly varied biochemical and metabolic phenomena but by a few, universal metabolic issues such as the APR and those highlighted in Entry Level Clinical Nutrition™. In turn, the authors of this body of literature, who use descriptors such as “sickness behavior” and “sick syndrome” maintain that what we are seeing in our chronically ill patients is not “disease” in the classic sense but a logical and predictable set of responses to a series of metabolic and environmental stressors. Furthermore, if we can address the causes of these responses such as low grade chronic metabolic acidosis, insulin resistance, inflammation, protein/amino acid deficiency, etc. significant improvements in chief complaints will, more often than not, follow.
MNR Report #234 – 08/01/2010 – PDF Version
- Bengmark S. Acute and “chronic” phase reaction – a mother of disease. Clin Nutr. 2004;23:1256-1266.
- Lowenstein C & Matsushita K. The acute phase response and atherosclerosis. Drug Discovery Today:Disease Mechanisms. 2004;1(1):17-22.
- Ebersole JL & Cappelli D. Acute-phase reactants in infections and inflammatory diseases. Periodontology. 2000;23:19-49.
- Gabay C. Interleukin-6 and chronic inflammation. Arthritis Research & Therapy. 2006;8(Suppl 2):S3.
- Cronstein BN. Interleukin-6: A key mediator of systemic and local symptoms in rheumatoid arthritis. Bulletin of the NYU Hospital for Joint Diseases. 2007;65(Suppl 1):S11-5.
- Summers GD et al. Rheumatoid cachexia: a clinical perspective. Rheumatology. 2008;47:1124-1131.
- Jensen GL. Inflammation: roles in aging and sarcopenia. JPEN. 2008;32(6):656-9.
- 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.
- Raj DSC. Role of interleukin-6 in the anemia of chronic disease. Semin Arthritis Rheum. 2009;38:382-388.