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' emphasizes the potential imperfections of L-T4 replacement
therapy that may lead to
hypothyroidism in some tissues such as the brain, while others (eg 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.