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.
