In this study, we found that the stress hormone, NPY, was statistically elevated in plasma from CFS cases compared to healthy controls - and to a group of patients with another fatiguing, multi-symptom illness, GWI. This later finding was unexpected. However, it might be explained by gender distribution, which was very different between CFS and GWI. ROC analysis indicated that plasma NPY has promise as a biomarker for distinguishing CFS both from healthy controls and .from related fatiguing illnesses. Our finding that NPY positively correlated with perceived stress, anger, depression, negative thoughts and maladaptive coping in patients with CFS suggests that NPY will be useful in defining subsets of patients for clinical trials and as a measure of therapeutic effects.
Abnormalities of the stress response are potential triggers or mediators of CFS symptoms . Acute stress induces a fight-and-flight response that prepares the organism for coping with environmental challenge . Sympathoadrenal activation during the stress response results in increased release of epinephrine (E) and norepinephrine (NE) from the adrenal medulla, increased NE and NPY release from the sympathetic nerve endings and changes in blood flow to a variety of organs . Activation of the hypothalamic-pituitary-adrenal (HPA) axis results in increased secretion of glucocorticoids from the adrenal cortex .
Glucocorticoids regulate immune cell reactions to the stressor. In the brain, stress responsive neurotransmitter systems, in interaction with glucocorticoids, modulate affect, cognition and anxiety, and suppress behaviors that are inadequate for the situation, such as eating and reproduction. Increased noradrenergic activity in the brainstem increases vigilance and alertness and promotes memory for threatening stimuli . These acute stress responses represent regulatory mechanisms that are critical to survival and adaptation of the species. Dysfunction in the regulatory capacity or interplay of these systems, as a potential consequence of dispositional risk or physical, chemical or emotional challenges, might plausibly exacerbate symptoms of CFS.
Immune activation and inflammation are postulated to be principle components in the pathophysiology of CFS [19, 20, 51]. Inflammatory responses are controlled by the HPA axis network that involves corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol. Normally cortisol induces a down-regulation of inflammation. However, this mechanism is disrupted in the typically hypocortisolic CFS patient . Broderick and colleagues propose that this disruption results not only from the possible failure of individual neuro-immune components but also involves a spontaneous restructuring of the control network . Van Houdenhove and co-workers have formulated the hypothesis that the HPA axis hypofunction in CFS reflects a fundamental and persistent dysregulation of the neurobiological stress system . Dysautonomic conditions (e.g., neurally mediated hypotension or orthostatic intolerance) have been reported in CFS patients as well as the related syndrome, GWI [54, 55].
A recent study from our group demonstrated reduced stroke volume and cardiac output in more severely afflicted CFS patients . Although we did not measure cortisol in the present study, we and others reported that moderate hypocortisolism occurs in CFS, and that it is of clinical relevance [57, 58]. For example, CFS cases with low cortisol have a poorer response of CFS cases to cognitive behavioral stress management . Of interest is the finding of Kempna, et al. , that NPY inhibits the production of cortisol in human adrenal H295R cells via the Y1 receptor. Antonijevic and colleagues showed that administration of NPY reduced cortisol secretion during night hours in healthy subjects . In contrast, a series of experiments by Morgan, et al. demonstrated that acute, uncontrollable psychological stress elevated plasma NPY as well as plasma cortisol in healthy subjects [61, 62].
Recently, our group reported that soluble as well as cell surface associated dipeptidyl peptidase IV (DPPIV) is decreased in CFS cases relative to controls . NPY's biologic effects require interaction with its receptors. Native NPY 1-36 in the periphery is a major mediator of stress, responsible for prolonged vasoconstriction via Y1 receptors . By cleaving the N-terminal Tyr-Pro dipeptide from NPY, DPPIV generates the Y2/Y5 receptor agonist NPY 3-36, that loses its affinity for the Y1 receptor and is angiogenic and inhibitory of NE release [30, 63]. The low DPPIV observed in CFS coupled with high NPY would favor the Y1 receptor agonist form of NPY.
Another consideration of interest regarding NPY and CFS is the possibility of chronic viral infection in some patients. Du, et al , recently described increased NPY expression in the central nervous system (CNS) of mice following infection with a neurovirulent polytropic retrovirus. This virus infects macrophages and microglial cells resulting in production of proinflammatory cytokines , including interleukin 1 alpha (IL-1α), IL-β, and Il-6 known to be elevated in CFS . Viral triggers such as EBV and HHV6 have long been suspected of involvement in the onset and persistence of CFS [3, 5, 6]. Evidence of xenotropic murine leukemia virus - related virus (XMRV) in peripheral blood mononuclear cells (PBMCs) in the majority of CFS cases, but not controls, supported the viral infection hypothesis . This report by Lombardi, et al was followed by 4 subsequent reports of failure to detect any murine leukemia virus (MLV)-related virus gene sequences in blood from CFS patients [12, 14, 66, 67] and one report of MLV-like virus gag gene sequences, but not XMRV, in 86.5% CFS cases compared with only 6.8% of healthy volunteer blood donors .
An obvious limitation of this study is that the samples represent a single point in time. We are presently conducting longitudinal studies. As Broderick and colleagues have pointed out, biomarkers measured in human subjects tend to be highly variable. These indicators are parts of a complex and integrated system and their inter-dependency must be addressed. The effect of medications such as cholesterol lowering, pain or anti-depression on plasma NPY is not known. However, cholesterol-lowering drugs are not well tolerated in CFS patients. Patients on opioid pain medications were excluded from the study. The effect storage of plasma for up to 5 years at -80°C on RIA detectible NPY is not known.