Glimpse of an elusive diagnostic biomarker for Chronic Fatigue Syndrome


The clinical entity of Chronic Fatigue Syndrome1 (CFS) has so long eluded explanation. Patients of CFS complain of extreme and prolonged fatigue that is disproportionate to their physical and mental activity, and is not alleviated by any amount of rest. The condition may well last for more than 6 months at a time, and may be accompanied by a variety of other symptoms, such as pain in the muscles and/or joints without swelling, memory impairment, significant lapse of concentration, headaches, painful lymph nodes in the neck or armpit, and so forth. Physicians currently employ the 1994 case definition in which persistent (>6 months) fatigue is to be present along with at least 4 of 8 known associated symptoms, for the condition to qualify as CFS; if these criteria aren’t fully met, the condition is referred to as ‘idiopathic’ (without known cause) fatigue. Management of both conditions are practically identical.

For patients of CFS, the bouts can be debilitating, perhaps made worse by the fact that scientific research has not yet identified the root cause of the condition, and can, therefore, offer no solution beyond symptomatic relief.

Many theories as to the cause of CFS abound, such as:

  • Direct effect of viral infections;
  • Specific induction of host immunity as a result of invasion by some pathogenic microbe, et cetera.
  • Non-specific activation of the patients’ immune systems, a subset of which may be expressed as allergies;
  • Direct involvement of the central nervous system, resulting in abnormal, neurally-mediated lowering of blood pressure, which may cause light-headedness and compensatory tachycardia (i.e. increase in heart rate);
  • Indirect action of the brain, via the HPA (‘Hypothalamic-Pituitary-Adrenal’) axis, which may disturb the release of various stress-associated hormones.

In addition, symptoms in CFS may resemble those seen in many physiological, neurological, as well as psychological illnesses.

This, understandably, poses a diagnostic challenge; the problem is that all these phenomena in the human body are processed through physiological pathways that are highly inter-related, a fact which underscores the difficulty in arriving at a single factor responsible for CFS. Current thinking is, therefore, that CFS may be multi-factorial, i.e. triggered by a combination of an unknown number of factors.

In part, this is also the reason why there is no diagnostic test or ‘biomarker’ (an observable phenomenon that can be specifically attributed to the condition) for CFS, and why the diagnosis must be exclusionary, via a process of elimination of other possible conditions that may explain the symptoms. What makes diagnosis even more difficult – not to mention, controversial – is that the number, types and even severity of these symptoms are highly variable amongst patients, and the condition periodically goes into remission and relapses.

When symptoms arise, management – in absence of a cure – focuses on treating primarily those symptoms that disrupt life and activities most, such as pain, lack of sleep, memory problems, depression, anxiety, et cetera. Long term care involves specially-developed activity programs, behavioral therapy and other interventions that aim to mitigate the physiological and psychological effects of this chronic illness.

Given that many CFS symptoms mimic those of certain immune dysfunctions involving unregulated inflammation, a lot of research has focused on understanding the inflammatory pathophysiology of CFS patients. One recent study from the Stanford University medical school, published in the Journal of Translational Medicine2, investigated the role of cytokines in this condition. Cytokines are a group of small protein molecules produced and released by various types of cells in the body, including cells which comprise the immune system. Cytokines take part in cell-to-cell signaling; released by one type of cells, cytokines affect other cells, either in their immediate environment or elsewhere in the body, by binding to receptor molecules present on the surface of these cells. These receptors recognize specific cytokines, and the binding at the cell surface initiates cascades of sub-cellular (inside the cell) biochemical reactions which lead to a specific effect. For example, some cytokines are active in regulation of developmental processes3 during the implantation of the embryo and maintenance of pregnancy. Again, ‘pro-inflammatory’ cytokines, released by certain leukocytes of the innate immune system, can recruit other leukocytes and bring them to the site of infection or injury, in order to mediate various effects4.

The Stanford group, led by Elizabeth Stringer, hypothesized that the daily variability of the levels of various cytokines in the serum may correlate with the observed variations in the severity of CFS symptoms. In a pilot study they had monitored the daily levels of 51 different cytokines in 3 women with fibromyalgia (another chronic painful condition) and CFS, and discovered that one adipokine (cytokine released by fat cells, ‘adipocytes’), called Leptin, stood out. Leptin, which regulates appetite, metabolism and behavior5, and has profound inflammatory effects, as well as a protective role in mucosal immunity6, was found to correlate significantly with the self-reported fatigue severity.

In the current study, participants (CFS patients and healthy controls, all female) were chosen carefully to account for or exclude other existing conditions that may confound (i.e. not allow proper interpretation of) the observations. Twice a day, 20 participants answered questions about the severity of fatigue, muscle/joint pain and sleep quality that they experienced during the study period, which included blood draws for 25 consecutive days. In the CFS patients, serum Leptin levels correlated strongly with daily levels of fatigue; although Leptin levels were associated with a plethora of pro-inflammatory cytokines, no other direct correlation was found, indicating that Leptin may be the central player in the CFS-associated inflammatory process mediated by a network of cytokines. None of these associations were observed in healthy controls. Leptin levels were predictive of daily fatigue levels in women with CFS, and using cytokine predictors, the authors were able to distinguish between high fatigue and low fatigue days with 78% accuracy.

Leptin Fatigue Correlation
Illustrative image composite made from parts of Fig. 2 & 3 of Stringer et al. (Ref. 2)

Interestingly, absolute Leptin levels, as well as the range of daily fluctuations, were not abnormal in CFS patients, which suggests that Leptin alone may not be responsible for causing the inflammation in CFS. As the authors indicate, larger and more detailed studies are necessary to explore a causal role of Leptin and/or its cytokine network in driving CFS severity, and uncover hitherto elusive diagnostic biomarker(s) and therapeutic targets.


Further reading:

  1. CDC information website on Chronic Fatigue Syndrome.
  2. Stringer, EA, et al. Journal of Translational Medicine 2013, 11:93; doi:10.1186/1479-5876-11-93.
  3. Saito, S. Journal of Reproductive Immunology 2001, 52:15-33; PMID: 11600175
  4. Whitney, NP, et al. Journal of Neurochemistry 2009, 108:1343-59; PMCID: 2707502.
  5. Gautron L, Elmquist JK. Journal of Clinical Investigation 2011, 121:2087-93; PMCID: 3104762.
  6. Mackey-Lawrence NM, Petri WA Jr. Mucosal Immunology 2012, 5:472-9; PMCID: 3425733.

One Response to “Glimpse of an elusive diagnostic biomarker for Chronic Fatigue Syndrome”

  1. Kelly Latta Reply | Permalink

    Thank you for this well written post. There are more current diagnostic criteria (Carruthers et al 2011) which focuses on post exertional fatigue which is a key symptom of Myalgic encephalomyelitis, sometimes called chronic fatigue syndrome). It would be interesting to know if the Leptin correlated with this specific symptom that last 24 hours or longer and is unrelieved by rest. Dr. Christopher Snell, an exercise physiologist/ME and CFS expert, who spoke at this past weeks FDA workshop has done research (Davenport et al 2011) indicating immune abnormalities, sleep disturbance and pain accurately classify 92% of individuals with CFS and 88% of control subjects making a less heterogeneous group.

    As for biomarkers, there are biomarkers for subgroups. At the same FDA meeting immunologist Dr. Nancy Klimas, who is was also on an FDA panel of experts, said they have substantiated biomarkers in subgroups. (Klimas NG et al 2012; Brenu EW et al 2013).

    With a trend toward larger cohorts and more selective chosen cohorts studies should have sufficient statistical power to tease out some of these subtleties.

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