Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in [ME, FM], 2025, Azimi, Moreau+

SNT Gatchaman

SNT Gatchaman

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Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia
Azimi, Ghazaleh; Elremaly, Wesam; Elbakry, Mohamed; Franco, Anita; Godbout, Christian; Moreau, Alain

Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations.

In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0–50 pg/mL), normal (51–200 pg/mL), and high (>200 pg/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM.

Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM.

These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.

Web | PDF | International Journal of Molecular Sciences | Open Access
 
SNT Gatchaman said:
Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia
Azimi, Ghazaleh; Elremaly, Wesam; Elbakry, Mohamed; Franco, Anita; Godbout, Christian; Moreau, Alain

Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations.

In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0–50 pg/mL), normal (51–200 pg/mL), and high (>200 pg/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM.

Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM.

These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.

Web | PDF | International Journal of Molecular Sciences | Open Access
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Does this have similar methodological issues to the other recent Moreau paper?
 
4.3. Post-Exertional Malaise Provocation and Symptom Assessment
To evaluate PEM in a standardized setting, participants underwent a validated passive stress protocol initially designed for ME patients [77]. This involved 90 min of mechanical stimulation using an ABR therapeutic massager with pulsatile compression cuffs applied to one arm (0–4 psi at 0.006 Hz). PEM severity was subsequently quantified five days later, using the DePaul Post-Exertional Malaise Questionnaire (DPEMQ) [78,79].
Click to expand...
77 is this:
 
Social media summary:

1) A new paper found a slight increase of Fibroblast growth factor 21 (FGF-21) in ME/CFS patients compared to controls.

FGF-21 is a hormone-like protein that helps to regulate metabolism and has been found to be increased in previous ME/CFS studies.

2) Below is the data from the new Canadian study. There were 49 patients with fibromyalgia (FM), 99 with ME/CFS, 104 with both ME/CFS and FM, and 54 healthy controls.

As you can see, the difference is not large with lots of overlap between groups.

1756715583049.png

3) But FGF-21 has been found to be increased before in ME/CFS, most notably by the Norwegian group (Hoel et al. 2021). They speculated that this might reflect a metabolic compensation mechanism in response to tissue hypoxia.

1756715597353.png

Reference:
https://pubmed.ncbi.nlm.nih.gov/34423789/

4) In a later publication (Hoel et al. 2025) it seemed that the Norwegian group replicated these results in a larger sample of more than 200 patients from the Cure ME/CFS Biobank.

1756715609862.png

Reference:
https://medrxiv.org/content/10.1101/2025.05.28.25328245v1

5) FGF-21 is a metabolic stress hormone and increased levels have been found in conditions such as obesity, mitochondrial myopathies, and type 2 diabetes.

Perhaps it's a subtle signal that points to an underlying metabolic issue or a compensation mechanism in ME/CFS.
 
I wonder with results like this if repeated tests on the same patients whilst monitoring activity and PEM would help. If this represents metabolic stress wouldn't the levels change as severity of symptoms change?
 
Looking at the study and the comments by @ME/CFS Science Blog on FGF21, I would like to share some potentially helpful additions.

@ME/CFS Science Blog mentions that FGF21 "is a metabolic stress hormone and increased levels have been found in conditions such as obesity, mitochondrial myopathies, and type 2 diabetes". Ideally we would like to know how FGF21 is related to what we know about ME/CFS.

Here is one way I tried : I Introduced the GWAS findings and asked AI how it all connects with elevated FGF21. Some snapshots from the answer :

First, ER Stress :
ER Stress.png


also, hepatic involvement (cc @Chris Ponting ), oxidative stress and immune function :

oxidative_stress.png

Also an interesting connection with Peroxisome proliferators :


transcriptional_epigenetc.png

Please note the mentions on PPARa, Liver, PPARγ. Interestingly, a network analysis performed in 2017 shows those concepts, as well as oxidation and also identified a specific phospholipid, namely Choline :

network2017.jpeg



Of note, ER Stress was one of the first concepts identified by machine learning in 2015, as potential research targets.
 
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