The CFS Holy Grail: THE biomarker

Over the last 16 years that I have been active dealing with my own CFS and while in remission, trying to understand this horrible puzzle more, I have come across many, many publications about finding a new biomarker for CFS.

IMHO, there is no SINGLE biomarker. The belief that there will be a single biomarker comes from the belief that the cause is a single item. A shift of the microbiome is not a single item. CFS is a a shift of dozen, in some cases, hundreds of relationships between many bacteria. There is no one bacteria or one virus or one DNA mutation responsible. The chemicals produced by these bacteria (metabolites)  may change, with certain ones being common across CFS patients. These same metabolities may also be common with some other diseases. The criteria to be a good biomarker is that it is unique to CFS and not to any other diseases. Almost all of these biomarkers are found by comparing CFS to healthy individuals.

Today, a read forwarded an article about Activin B being a potential biomarker. The article is Activin B is a novel biomarker for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) diagnosis: a cross sectional study [2017]. “Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval….Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. … follistatin levels were significantly lower in the CFS/ME group (p < 0.0001) ”

So what is Activin A and B? There is a wikipedia article on it. In short, it’s a chemical produced by cells.

What do we know from PubMed:

  • “Higher than normal values of these proteins[Activin A and B] were common in patients with H1N1 infection” [2014] So we know that virus can increase…
  • “We also show, for the first time to our knowledge, that IL-1β up-regulates hepcidin by an unexpected mechanism involving increased expression of BMP2 or activin B and consequent activation of the BMP signaling pathway… we found that IL-1β induced a significant increase in expression of activin B in mouse liver… may not apply to humans….Firstly, IL-1β has been implicated in the pathogenesis of IBD by several observations. ” [2015]
  • “Our results correlate and support the previous findings as there was a significant decrease in serum follistatin and significant increase in serum activin-A, activin-B, …  in patients with chronic hepatitis C and who did not receive treatment compared to healthy controls.” [2014] – So this diseases pattern shifts matches 2 of the 3 reported.
  • “Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation.” [2012]
  • “One of the BMP receptor ligands that appears to play a role in the inflammation-induced elevation of hepcidin is activin B.” [2015]
  • “Follistatin is a specific activin-binding protein and blocks the action of activins in most biological systems by preventing the binding of activins to their type II receptors (23).” [2009]

Bottom Line

Activin B is involved with inflammation — CFS has inflammation (as do hundreds of other conditions).  Comparing a group of patients with prolonged inflammation to healthy controls is likely to produce a positive result. Does this result show CFS? No, it shows inflammation — which is already well established by past studies with CFS/FM etc.

The low level of Follistatin reported is far more interesting because it keeps the Activin in control.  Follistatin-like protein has been implicated in Lyme arthritis [2014] . “Whether the associations between fT4 and follistatin levels persist in the whole thyroid function spectrum warrants future investigation.” [2016]

So, will this become a biomarker for CFS — very unlikely. Indirectly, we see that the inflammation chemicals increases Activin B and the decrease of follistatin decrease thyroid function. I would not be surprised to see a study finding high Activin B and low follistatin is associated with thyroid syndromes and thus this biomarker lacks the ability to separate them apart.