In Search of Lost Volume: The Potential Causes of Hypovolemia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Hypovolemia and orthostatic intolerance are hallmark features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) but remain incompletely understood. This review summarizes the physiological control of intravascular volume and discusses how these mechanisms may be disturbed in ME/CFS. Reduced intravascular volume limits cardiac filling and perfusion. Both main volume-regulating systems—vasopressin and the renin–angiotensin–aldosterone system (RAAS)—appear impaired. Low vasopressin despite hypovolemia may result from disturbed serotonergic-, noradrenergic- and angiotensin II–mediated stimulation of vasopressin. RAAS activation is blunted despite volume depletion. Excessive release of vasoactive mediators from metabolically impaired skeletal muscle may cause renal sodium and water loss, but suppress compensatory renin secretion, and increase microvascular permeability, along with elevated levels of cytokines, reactive oxygen species (ROS), and potentially hypoxia-inducible factors (HIFs). Dysfunction of ß2-adrenergic receptors weakens their physiological role in inhibiting microvascular leakage and impairs sodium absorption via the main transporter, sodium-proton-exchanger subtype 3 (NHE3). Exercise-induced fluid shift into the intracellular skeletal muscle compartment appears exaggerated due to intracellular accumulation of osmolytes due to the poor energetic situation resulting from the combined effect of poor perfusion and mitochondrial dysfunction. Collectively, hypovolemia arises from interacting volume regulatory disturbances, is amplified by exertion and contributes to post-exertional malaise.