The CDC’s Pharmacogenomic’s Studies II: The Allostatic Stress In CFS

Allostatic Load is Increased in CFS?

Maloney, E., Gurbasani, B., Jones, J., Coelho, L., Pennachin, C and B. Goertzel. 2006. Chronic fatigue syndrome and high allostatic load. Pharmacogenomic 7 (3), 467-473.

Four research groups examined the data generated by the CDC from the two day Wichita Hospital stay. In order to determine if signs of an altered stress response were present the Maloney-Goertzel group measured components of allostatic load in CFS patients.

ALLOSTATIC LOAD

When something – in technical terms a ‘stressor’ – threatens the healthy equilibrium of the body (its homeostasis) the body uses hormones, neurotransmitters and cytokines in order to maintain within a narrow range such vital physiological parameters such as pH, temperature, glucose levels and blood oxygen levels (McEwen 2004). Many things can be stressors: infection, low blood sugar, low tissue oxygenation, extremes of heat or cold, extended exercise, wounds, pain, psychological distress, etc. are all stressors. The process of maintaining homeostasis – the state of the body’s equilibrium – in the face of a threat is calledallostasis.

Normally, when the threat diminishes, the production of these agents ceases and they are either metabolized or removed from the intracellular spaces. But what happens if either the threat or the threat response is not temporary? McEwen proposes that a chronic activation of the stress response system will lead to an overproduction or underproduction of the main stress mediators mentioned above. Ultimately a chronic activation of the stress response system can lead to tissue damage or receptor desensitization. Indeed, increased levels of allostatic stress have been associated with increased mortality and disease. The damage caused by an over- or under-active allostatic stress response is called allostatic load.

Allostatic stress is usually quantified using hormonal and immune variables that researchers believe are indicative of a disturbed homeostasis. In past studies these have included cortisol, CRH, ACTH, serotonin, fibrinogen, thrombin, anti-thrombin, IL-6, C-reactive protein, creatinine, albumin, among others.

An interesting corollary of the above definition is the idea that a body can respond effectively to a threat, say an infection, and still become ill if the stress response is not turned back down. It may be that the triggering agent is often superfluous – the pathogen, trauma, etc. that triggered the aberrant stress response may be long gone before the problems of allostatic load occur. This brings up the somewhat odd scenario of a person responding effectively to a stressor but still getting ill because a problem with an over-long or over-aggressive stress response. Alternatively, where the stress response is inadequate to respond to the threat, the damage caused comes from the stressor itself.

Allostatic Research: a short history The theory of allostatic stress is relatively new but studies of the effects of allostatic load (AL) are increasing; twenty-nine papers were published on AL in 2003, 19 of them studies. Most efforts have attempted to characterize the contributions aging and social/psychological stress play in increasing allostatic loads. Increased levels of psychological stress have been shown to increase allostatic load, but social stress studies have had mixed results. Aging has been shown to be associated with increased allostatic load. This appears to be one of the first studies to characterize levels of allostatic stress in a specific disease.

Increased levels of allostatic load have been associated with increased risk of death, heart disease, cognitive problems and worsened physical functioning in prospective studies. AL was predictive of both physical and cognitive decline in one study.

Altering the Allostatic Stress Response - McEwen cites four ways the stress response can be deregulated (McEwen 2000).

  • repeated exposures to stressors (infection, low blood volume, low blood glucose levels, psychological stress, etc) can result in the stress response system being chronically turned on.
  • The inability of the body to metabolize or clear stress agents such as hormones or neurotransmitters from its system can lead to the stress response being chronically turned on.
  • A overly sensitive stress response system that on a hair trigger can be chronically turned on.
  • A stress response that is under-responsive will leave the body vulnerable to the effects of stressors.

Why focus on the stress response in CFS? One reason is surely the low levels of the main adrenal stress hormone cortisol commonly found in CFS. Another may be the different triggers for the disease. Prospective studies have identified three pathogenic triggers (EBV, Coxiella burnetii, Ross-River Virus). Other studies have indicated increased psychological stress can predispose one to CFS and anecdotal reports indicate that toxin exposure, anorexia nervosa and pain (physical trauma) may as well. (Of course many CFS patients cannot point to a physically or psychologically troubling factor that preceded their CFS). Given the disparate nature of these triggers it is not illogical to posit that something as fundamental as the stress response is disrupted in CFS. The immune activation, the dominant Th2 immune response, the atypical depression, the problems with orthostatic intolerance, sleep and exercise could all have links with an altered stress response.

The consensus regarding the HPA axis and CFS seems to be that CFS patients mostly display a ‘mild hypoactivity’ or under-responsiveness of the HPA as evidenced by reduced ACTH or cortisol levels. There is as yet no indication, however, how a ‘mild’ HPA axis hypoactivity can account for the level of debility seen in this disease. (SeeHypocortisolism, Artifact or Central Factor in CFS?)

Methods The authors of this report wanted to know if a) CFS patients demonstrated indications of increased allostatic load and b) if it was present which systems it was present in.

The markers of allostatic stress Maloney et. al. chose were simple; metabolism – waist/hip ratio; cardiovascular system – blood pressure, aldosterone; immune system – c reactive protein, albumin, IL-6; HPA axis – cortisol, DHEA-S, sympathetic nervous system – norepinephrine, epinephrine.

Findings This study found that CFS patients expressed a trend towards having higher levels of allostatic load than the controls (P<.06).  Statistically speaking this number is not particularly strong; the lowest level of probability deemed ‘significant’ is p<.05. It indicates there is a 6% chance that CFS patients do not have increased allostatic load relative to the controls. What researchers really like to see is a level of probability that is a magnitude or more greater (i.e. p<.005).

This study found that three components of allostatic load, waist/hip ratio, aldosterone and urinary cortisol best differentiated the CFS patients from the controls.

 Waist/hip ratio - We knew the CFS patients were rather stout but since they were paired with equally stout controls increased obesity could not account for the increased waist/hip ratios seen. Instead the authors believe they are probably due to an impaired metabolism that results in the increased production and accumulations of fat in the midsection. This type of fat is believed to be more biologically active than fat found elsewhere.  Increased waist/hip ratio’s increase the risk for heart disease and diabetes. A recent study found waist/hip ratio’s were three times more effective in predicting the risk of heart attack than the traditional measure of obesity, body mass index.

Aldosterone is the principle mineralocorticoid hormone produced by the adrenal cortex; It influences water and electrolyte (particularly sodium and potassium) metabolism and balance. Aldosterone’major job is to facilitate potassium exchange for sodium causing sodium reabsorption and potassium loss. It could play a role in the low blood volume present in some CFS patients. Increased aldosterone levels are implicated in cardiovascular disease, inflammation and increased oxidative stress. The authors believe it could signal an altered energy ‘set point’ of the body.

Cortisol, a product of cortisone, is the most abundant hormone secreted by the adrenal glands and the most potent one.An antagonist to insulin cortisol promotes the breakdown of lipids, and proteins in order to increase blood glucoseconcentrations. (Insulin promotes glucose uptake by the tissues).  A key modulator of the immune system cortisol is also an important anti-inflammatory agent. Reduced levels of cortisol could, conceivably result in increased inflammation and a predisposition for autoimmune diseases. (See Hypcortisolism: Artifact or Central Factor in CFS?).

Brain Damage Causes the Increased Allostatic Load in CFS?

The researchers hypothesized that the energy ‘set point’ of brains of CFS patients is too low. The theory that abnormal energy ‘set points’ can lead to disease was set out in a paper called ‘The Selfish Brain: Competition for Energy’ published in 2004. See Selfish Brains In CFS? .

This theory, which is quite complicated, posits that a disrupted stress response can cause the brain to either pull too much or too little energy (glucose) from the body. In the case of CFS, these researchers believe the lowered cortisol levels caused by chronic stress due to infection, psychological stress, etc. may have caused the brain to under-respond to its own energy deficiencies. This low energy ‘set point’ would cause decreased glucose metabolism in the brain, disrupted signaling of the main neurotransmitter in the brain, glutamate, and increased body mass due to increased glucose allocation and appetite. One way the brain tries to get more glucose is to activate the feeding centers of the brain.

Evidence – Although the authors do not cite it, there is some evidence for altered glucose metabolism in CFS. A 2003 study by Seissmeir found impaired cerebral glucose metabolism in different parts of the anterior cingulate region of about half the CFS patients tested. A correlation analysis that found, however, that the reduced glucose metabolism was associated not with fatigue or quality of life measures but with depression and anxiety, suggested it was due to the stress from the disease rather than an integral component of it. This is interesting given the inability of these variables in the below study to correlate with the levels of fatigue in CFS (see below).

The 2003 Vernon gene study that attempted to differentiate subsets in CFS highlighted the possible importance of metabolism for some CFS patients. It found that genes involved in glycolysis and glucose metabolism as well as purine and pyrimidine metabolism and oxidative phosphorylation best differentiated CFS patients with gradual onset from those with sudden onset.

The Future - Despite its relatively poor performance statistically the CDC was impressed enough with the results that a larger study with more extensive cardiovascular measures is planned.

We will apparently know sooner rather than latter whether our brains are selfish or not. The authors end up the article by stating that ‘in the near future we will determine the usefulness of this model in determining the pathophysiology of CFS’ and suggest their results could lead to a biomarker for CFS. If a biomarker is found it will likely be a simple and relatively cheap one to determine as it appears it will consist of a formula that describes levels of commonly measured substances such as cortisol, aldosterone, etc.

Proof For and Not For The Theory; Some Symptoms in CFS are Correlated with Allostatic Load

Goertzel, B., Pehnachin, C., Coelho, L., Maloney, E., Jones, J. and B. Gurbaxani. 2006. Allostatic Load is associated with symptoms in chronic fatigue syndrome patients. Pharmacogenomics 7, 485-494.

The Maloney paper found that CFS patients demonstrated a higher allostatic load than did healthy age, sex, race and body mass index controls. Often the next step with a finding like this is to see if it is correlated with debility. If allostatic load is a real factor in CFS then patients with more severe CFS should have higher allostatic loads and those who are healthier should have lower allostatic loads.

This study used statistical tests to determine if indices of debility in three areas (fatigue, pain, general symptom intensity/frequency using three self-scored tests (SF-36, MFI, SI)) were correlated with measures of allostatic load (waist/hip ratio, aldosterone, blood pressure, cortisol, etc.). They did this by comparing the scores of CFS patients with high levels of fatigue with low levels of fatigue, etc.

This study found allostatic load did not correlate, interestingly enough, with fatigue but was very significantly correlated with body pain (p<.009), and moderately correlated with physical functioning (activity levels) (p<.02) and symptom severity (p<.05). This suggested that allostatic load does contribute to these symptoms but not to fatigue.

Fatigue, particularly post-exertional fatigue, is the hallmark of CFS. Pain, on the other hand, is not a hallmark but four of the eight symptoms in the CDC definition of CFS are associated with pain, and of course, CFS bears many similarities to Fibromyalgia, perhaps the quintessential pain disease. Impaired physical functioning is an important part of CFS. It is unfortunate that post-exertional fatigue is rarely assessed in these studies. These findings suggest, however, the markers of allostatic load measured, while important, are secondary rather than primary features of CFS.

 

The researchers then used a different statistical technique to determine which measures of allostatic load contributed most to each kind of debility. They found that high levels of c-reactive protein, a marker of inflammation, were the best predictors of body pain; that increased levels of two sympathetic nervous system catecholamines, norepinephrine and epinephrine and diastolic blood pressure best predicted impaired physical functioning. All three of these are involved in maintaining blood flows to the tissues during exercise.

Two markers of cardiovascular functioning, systolic blood pressure and aldosterone, best predicted high symptom severity. The authors noted that (way back in 1993) one study found evidence of increased levels of angiotensin converting enzyme (ACE) activity were found in CFS patients. Like so many other promising studies no follow up studies were ever done. They cite another paper in this volume that found altered R-R intervals.

A Spotlight on the Cardiovascular system and Circulation – Surprisingly the only factor included in this study that has been more or less consistently abnormal in CFS – cortisol – did not appear to contribute greatly to the self-reported measures of debility in these CFS patients. Instead the other the arm of the stress response – the sympathetic nervous system (SNS) – showed up in spades. The SNS plays a large role in circulation, the cardiovascular system and immune regulation. Indeed almost all the factors noted in this study are involved in one way or another in cardiovascular functioning and circulation.

One of the key vasoconstricters in the body, norepinephrine (NE), helps determines the amount of blood flow to the tissues. Intriguingly given its possible role in impairing physical functioning in CFS patients it is secreted in response to physical stress and low blood pressure. Epinephrine (E), on the other hand, regulates heart rate and the force of the hearts contraction, the relaxation of bronchial and intestinal tissues and various metabolic activities. Increased SNS activity, not surprisingly, plays a major role in heart disease. Neither NE nor E have been well studied in CFS. Aldosterone effects blood volume and is implicated in hypertension and heart disease. That both systolic and diastolic blood pressure showed up in this analysis further suggests a cardiovascular component to CFS. Raised c-reactive protein levels are commonly found in inflammatory diseases and are considered a risk factor for heart disease.

More findings suggestive of impaired circulation have recently emerged. Natelson just published a study finding reduced cortical blood flows in CFS. Some researchers believe that altered SNS functioning in the muscles of FMS patients contributes to the pain found there. Given all this interesting data, one looks forward with increased anticipation to the big Hurwitz study on blood volume in CFS (that began in 2000 – a plague on all 6 year studies!) and the Peckerman study on systolic functioning that was supposed to have been published last year.

Not surprisingly, given the target placed on cardiovascular functioning in CFS by these findings, the authors state they will look more closely at the cardiovascular system in future studies.

CONCLUSIONS

Significant or Not? – It is unclear how significant these findings are. Yes, there are indications of increased allostatic load in CFS. Yes, they occur in two systems of interest in CFS, the cardiovascular and metabolic systems. While CFS patients do exhibit several characteristics one would expect to show up in a disease characterized by a disturbed stress response, namely low cortisol levels and signs of immune activation, the cortisol levels in CFS are only ‘mildly’ low (and not infrequently normal), and the results of cytokine studies have been inconsistent as well. We haven’t seen thus far a level of aberration that can in any way account for the debility seen in CFS. Of course these allostatic load studies are preliminary; they focused on broad measures of allostatic load spread across several systems. The next studies that focus more on specific systems should be the really important ones; they should begin to tell us whether these studies will be the beginnings of something really significant for CFS or whether they are merely the signs of a disease that is stressful in so many ways.

The Chicken or the Egg? – Given the difficulty in finding a central pathogen in CFS researchers have for many years tried to understand how a triggering event such as an infection could lead to such a long term chronic illness. An infection caused aberration in the stress response could provide a satisfactory model for many CFS patients.

A major unanswered question, however, is whether the stresses associated with having a chronic disease such as CFS causes the increased allostatic loads seen or if CFS is the result of an aberrant allostatic stress response? Does one try to remove the stressor (i.e. infection, toxin, psychological trauma, etc.?) or does one try to rebalance the stress response system? If, for instance, a chronic, albeit still undiagnosed infection is at the root of ones CFS then adjusting the stress response could prove detrimental (SeeHypocortisolism in CFS; Artifact or Central Factor?). If, on the other hand, the pathogen is simply an incidental trigger that caused the stress response to go haywire, then there is no sense in dealing the pathogen as it is likely long gone.

This second scenario is complicated by the possibility that an altered stress response could, through its deregulation of the immune response, allow the introduction of opportunistic pathogens that cause further problems; i.e. the pathogen one treats in CFS may not be the one responsible for the initial pathology. A similar scenario could be envisioned regarding the cardiovascular system. It is intriguing that researchers and physicians such as Dr. Cheney have posited almost from the beginning a scenario involving an initial and long term dysregulation involving the hypothalamus, a key player in the stress response.

A third scenario involves not an initial deregulation of the stress response but a slow decline over time due to the stresses accompanying CFS. There is some evidence for this: a prospective study found no HPA axis changes in EBV patients that still had increased fatigue six months after infection.

A Laymen’s Ravings- Metabolic syndrome and CFS – Are these researchers suggesting CFS patients have metabolic syndrome? People with metabolic syndrome have increased waist/hip ratios, elevated triglycerides, reduced HDL cholesterol, increased blood pressure, and increased blood glucose levels, increased sympathetic nervous system activity, low levels of growth hormone, high uric acid levels, increased leptin and lactic acid levels, high c-reactive protein, electrolyte imbalances, increased oxidative stress and increased fibrinogen, IL-6 and TNF-a. Most people with metabolic syndrome are obese but not all are – they can have normal weight as well. What they do display are increased levels of body fat, particularly around the midsection.

How do CFS patients compare to metabolic syndrome patients? Given the heterogeneous findings for many of these tests in CFS its hard to definitively say. Some CFS patients in some studies have exhibited increased waist/hip ratios, increased sympathetic nervous system activity, low growth hormone levels, high lactic acid levels, higher c-reactive protein levels, altered electrolyte levels, increased fibrinogen, IL-6 and TNF-a. Other studies have shown differently with regard to SNS activity, growth hormone, lactic acid, fibrinogen, Il-6 and TNF-a. Dr. Cheney has stated that his patients have low, not high, uric acid levels. Virtually all studies that I am aware of have indicated increased oxidative stress in CFS. At this point there do appear to be some broad similarities between the two syndromes.

One scenario for metabolic syndrome suggests it begins with the increased production of biologically active fat which triggers the production of the pro-inflammatory cytokines TNF-a and IL-6 which arethe major players in the increased inflammation, oxidative stress and insulin resistance seen. The same dysfunction of metabolism that spurs growth of fat cells in the midsection also over time contributes to poor health, degenerative conditions and premature death.

One could hardly suggest that CFS is metabolic syndrome; far more people have metabolic syndrome – 1/5th of the adults in the US – than have CFS. But could having CFS increase one’s risk for metabolic syndrome?

*Update - this raving at least had some basis. Dr. Maloney reported at the 2007 IACFS conference that about a third of CFS patients met the criteria for metabolic syndrome. Her report is summarized in Part I of the Overview of the Professional Conference (click here)

To Pharmacogenomics Introduction / Pharma II: Gene Expression /Pharma III Gene Polymorphisms/

Pharma IV : Subsets

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McEwen, B.2000. Allostasis, allostatic load, and the aging nervous system: role of excitatory amino acids and excitotoxity. Neurochemical Research 25, 1219-31.

McEwen B. 2004. Protection and damage from acute and chronic stress. Allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Annals of NY Acad. Sci 1032: 1-7.

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