A significant minority of patients with hypothyroidism report persistent symptoms despite achieving normal thyroid biochemistry after levothyroxine (L-T4) replacement. Four principal lines of thinking, which are not mutually exclusive, may explain this enigma. The “low tissue liothyronine hypothesis” emphasises the potential imperfections of L-T4 replacement therapy, that may lead to hypothyroidism in some tissues like the brain, while others (for example hypothalamus) are euthyroid. The “Somatic Symptom and Related Disorders hypothesis” draws attention to an incidental coexistence of a diagnosis of Somatic Symptom and Related Disorders in patients with treated hypothyroidism. The “autoimmune neuroinflammation hypothesis”, highlights the potential consequences of inflammatory mediators due to thyroid autoimmunity (the commonest cause of hypothyroidism) on the brain. The “comorbidities and psychosocial hypothesis” implicates a variety of physical and psychosocial factors that have been noted to be associated with a diagnosis of hypothyroidism, which may be primarily the cause of persistent complaints. Over the past twenty years a great deal of time and effort has been expended pursuing the “low tissue liothyronine hypothesis”, which has failed to yield results that translate to patient benefits. This has skewed the balance in clinical practice, in favour of pursuing answers relating to L-T4 and liothyronine combination treatment, while the alternative explanations have been downplayed and potentially useful interventions have been given insufficient attention.
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