Clinical Workup Biomarkers: Exclusion and Comorbidity
A critical category of biomarkers in ME/CFS evaluation are those used not to diagnose ME/CFS but to: (a) exclude common mimics, (b) identify actionable comorbidities, and (c) complete the diagnostic picture. Normal results from these tests are informative and expected in ME/CFS; abnormal results identify conditions requiring independent management.
1 Thyroid Function Panel
Thyroid function assessment (TSH, Free T3, Free T4) is mandatory in any ME/CFS workup to exclude hypothyroidism, the most important and common mimic of ME/CFS fatigue. Hashimotoβs thyroiditis (identified by elevated thyroid peroxidase antibodies, TPO-Ab) represents both a mimic and a comorbidity: it can coexist with ME/CFS without causing the full symptom profile, and its identification enables targeted management. Thyroid function is typically normal in ME/CFS; however, normal thyroid function is a necessary component of diagnostic certainty rather than a dismissible negative finding.
2 Ferritin (Iron Stores)
Iron deficiency, defined by low serum ferritin even with normal hemoglobin and serum iron, is a common, actionable, and frequently missed contributor to fatigue. Standard laboratory reference ranges for ferritin (typically \(\geq 12\)β15 ng/mL) are insufficiently sensitive for symptom-resolution purposes: most ME/CFS-experienced clinicians use a functional target of \(\geq 50\) ng/mL for ferritin, consistent with evidence that symptoms persist in iron-deficient states below this level. Ferritin should be included in all ME/CFS workups; iron repletion to this target is low-risk and may provide meaningful symptom benefit in deficient patients.
3 Vitamin D (25-OH Vitamin D)
Vitamin D deficiency is reported as highly prevalent in ME/CFS, attributed to activity limitations, indoor confinement, and sun avoidance. 25-OH vitamin D has immune-modulating effects mechanistically relevant to ME/CFS pathophysiology, including regulation of T-cell function and cytokine production. Standard thresholds apply: deficiency \(<\) 20 ng/mL, insufficiency 20β29 ng/mL. Correction of deficiency is recommended as standard of care.
β Contradicting evidence: a direct cohort comparing ME/CFS (n=92) with controls (n=94) by LC-MS/MS found ME/CFS patients had higher, not lower, serum 25(OH)D (60.2 vs. 47.3 nmol/L, p=0.001), largely supplement-driven, with no association between vitamin D and fatigue severity (Earl et al. 2017). That cohort was not severity-stratified, so whether the deficiency claim holds for the most housebound/very-severe patients (who plausibly have the least sunlight) remains an open question (Vitamin D Deficiency in Housebound ME/CFS: Premise vs. Direct Evidence). The evidence therefore does not support assuming deficiency a priori β a serum 25(OH)D measurement should guide supplementation.