The enigma of persistent symptoms in hypothyroid patients treated with levothyroxine: A narrative review

Abstract

Overt hypothyroidism [raised serum thyroid-stimulating hormone (TSH) associated with low serum-free thyroxine (FT4)] and subclinical hypothyroidism (raised TSH with normal serum FT4) affect 2%-10% of the population. 1 Autoimmunity is the cause of hypothyroidism in about 80% of cases. 1 While in most patients treatment with levothyroxine (L-T4) restores health, 10%-15% of patients do not regain their well-being after apparently adequate treatment with L-T4. [2][3][4] Persistent symptoms are non-specific and include fatigue, weight gain and mood changes. 1,5 Such symptoms may lead to multiple medical consultations, patient requests for inappropriate investigations and dissatisfaction with treatment. [5][6][7] Given the high prevalence of hypothyroidism, this loss of wellbeing in a significant fraction of patients causes considerable socio-economic burden 8 and clinical management can be difficult and frustrating both for patients and for clinicians. 7 The underlying causes for persistent symptoms are unclear. Here, we outline |

T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity

“…An individual with SSRD has a maladaptive reaction to a somatic symptom [66]. Perros et al [44] elegantly describe the sequence of affairs: "Patients with SSRD have multiple medical consultations and inevitably thyroid function tests are ordered." "Approximately 10% of SSRD patients may also have thyroid dysfunction, usually subclinical hypothyroidism.…”

“…The inability of LT4 to restore thyroid hormone physiology is aptly called the “low tissue T3 hypothesis” by Perros et al [ 44 ]. The name directly refers to the basic research by Escobar-Morreale et al [ 1 , 2 ], demonstrating in experimental animals that tissue T3 content could be normalized only by the combined administration of T4 and T3, not by T4 alone.…”

Thyroid Hormone Replacement in Total Thyroidectomized Patients: Symptomatic and Metabolic Effects of Levothyroxine Monotherapy

“…We can adequately correct biochemical euthyroidism in total thyroidectomized patients with levothyroxine (LT4) replacement therapy, but some of them still complain of disturbances in their psychological and physical well-being (1). The reason for this may be the absence of some T3 in their circulation (2).…”

Time to refresh thinking on the terminology and management of hypothyroidism?

“…Replacement therapy with L‐thyroxine is not universally successful at reversing all symptoms for people with hypothyroidism 1 . For such patients, current guidelines recommend looking for other co‐morbidities including hypoadrenalism, celiac disease, anaemia, hypercalcaemia, sleep apnoea, renal failure and other conditions.…”

“…If there are ongoing symptoms, recent focus has been on the possible utility of liothyronine. The timely review by Perros et al 1 argues about thinking beyond this narrow perspective to look at broadening potential treatments as well as expanding research ideas.…”