WHAT IS (GLA) CONCEPT?
The Gut – Liver – Autonomic (GLA) framework is a working disease concept that links:
- Metabolic stress (muscle & mitochondrial load)
- Vascular & endothelial stability (blood flow, Ang-2/Tie2, perfusion)
- SMPDL3B-driven membrane fragility – a key biomarker connecting inflammation to vascular instability
- Bile-acid & liver signalling (FGF-21, toxic bile-acid load, exploratory use of UDCA and TUDCA as supportive medications)
- Autonomic balance (POTS/OI, sympathetic vs parasympathetic tone)
In this model, the liver and bile-acid signalling are not the root cause of ME/CFS. They act as a regulatory bottleneck: when stressed, they amplify existing vascular, metabolic, and autonomic problems.
This is an evolving hypothesis, not an established medical model. The questionnaires on this site are built to explore how well real patients’ patterns line up with this framework.
The Mechanistic Chain (for those who want the deeper biology)
This model proposes the following cascade:
- Viral or inflammatory trigger activates innate immune receptors (e.g. TLR4).
- PKC → PI-PLC signalling is upregulated.
- SMPDL3B is cleaved from the cell membrane, reducing membrane stability.
- Endothelial dysfunction develops (leaky, constricted, NO-depleted blood vessels).
- Perfusion drops and tissues shift toward ischemic metabolism.
- Calcium overload and ROS bursts occur in stressed cells and mitochondria.
- ROS further increases PI-PLC and SMPDL3B loss, deepening the loop.
- Kidney volume regulation becomes unstable, worsening low blood volume and hypoperfusion.
- Hepatic strain and FGF21 elevation signal ongoing metabolic stress in the liver.
- Autonomic dysfunction (POTS/OI, sympathetic bias) further reduces stable perfusion.
These interlocking loops may help explain why symptoms can become chronic, and why exertion can trigger delayed post-exertional crashes.
Choose your questionnaire
You can start with the broader 30+ question pattern questionnaire or the shorter SMPDL3B-focused quiz. You can always come back later and do the other one.
Option 1 – Full Pattern Questionnaire (30+ questions)
A broader questionnaire that looks at multiple dimensions of your illness pattern, including:
- Baseline vs deep-crash PEM pattern
- Vascular and autonomic features (POTS/OI, brain fog, dizziness)
- Metabolic load, recovery, and “energy envelope” behaviour
- GI / liver / bile-acid–type symptoms
- How your overall pattern fits the GLA amplifier model
Recommended if you have the energy to answer more questions and want a more complete pattern overview.
Option 2 – SMPDL3B-Focused Questionnaire
A shorter quiz that concentrates on SMPDL3B-linked vascular and inflammatory features, including:
- Signs of endothelial fragility and microcirculatory issues
- Volume / kidney-type symptoms (low blood volume, salt/fluid responses)
- Inflammatory/reactive features that line up with SMPDL3B biology
Recommended if you are mainly interested in how SMPDL3B-linked vascular instability might fit your presentation, or if you’re too fatigued for the longer questionnaire.
If you’re unsure where to start, begin with the Full Pattern Questionnaire and come back to the SMPDL3B-focused quiz later.
Understanding Your Subtype
These pages expand on how your subtype is interpreted using the GLA model, with separate paths for patients and clinicians.
Important disclaimer
- These questionnaires are exploratory tools built around a patient-led hypothesis (the GLA / SMPDL3B model).
- They are not diagnostic tests and do not replace medical advice, investigation, or treatment.
- No medication (including UDCA or TUDCA) should be started, stopped, or adjusted based on these results without discussing it with a qualified healthcare professional.
- If you have worrying or rapidly worsening symptoms, please seek medical care and do not rely on this site.