Managing symptoms in hypothyroid patients on adequate levothyroxine: a narrative review

Abstract

The current standard of care for hypothyroidism is levothyroxine (LT4) monotherapy to reduce levels of thyrotropin (thyroid stimulating hormone, TSH) to within its reference range and amelioration of any symptoms. A substantial minority continue to report hypothyroid-like symptoms despite optimised TSH, however. These symptoms are not specific to thyroid dysfunction and are frequent among the euthyroid population, creating a therapeutic dilemma for the treating clinician as well as the patient. We present a concise, narrative review of the clinical research and evidence-based guidance on the management of this challenging population. The clinician may endeavour to ensure that the serum TSH is within the target range. However, the symptomatic patient may turn to alternative non-evidence-based therapies in the hope of obtaining relief. Accordingly, it is important for the clinician to check for conditions unrelated to the thyroid that could account for the ongoing symptoms such as other autoimmune conditions, anaemia or mental health disorders. Systematic and thorough investigation of the potential causes of persistent symptoms while receiving LT4 therapy will resolve the problem for most patients. There may be some patients that may benefit from additional treatment with liothyronine (LT3), although it is unclear as yet as to which patient group may benefit the most from combined LT4 + LT3 therapy. In the future, personalised treatment with LT4 + LT3 may be of benefit for some patients with persistent symptoms of hypothyroidism such as those with polymorphisms in the deiodinase enzyme 2 (DIO2). For now, this remains a subject for research.

Real world clinical experience with a new formulation of levothyroxine engineered to meet new and stricter regulatory requirements

“…Alternatively, a substantial minority of hypothyroid patients continue to report symptoms reminiscent of this condition, despite medically optimised LT4 treatment. 15 The phenomena observed in France and New Zealand following reformulation of LT4 products did not occur appreciably in our study.…”

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

“…The nature of hypothyroid symptoms tends to be non-specific and difficult to distinguish from other conditions or general suboptimal health [ 38 ]. This was nicely illustrated by a study in patients with newly diagnosed overt autoimmune hypothyroidism using a population-based case-control design [ 39 ].…”

Triiodothyronine alongside levothyroxine in the management of hypothyroidism?

“…fatigue, weakness, feeling cold, gastrointestinal disturbances, among others), despite successful normalisation of TSH to within its laboratory reference range. [22][23][24] These symptoms also tend to occur commonly in the euthyroid population, and provide poor discrimination between people with or without genuine thyroid dysfunction. Expert recommendations on the management of these patients stress the need to exclude other possible causes of these symptoms, before considering a thyroid-related aetiology.…”

“…Expert recommendations on the management of these patients stress the need to exclude other possible causes of these symptoms, before considering a thyroid-related aetiology. 23,25 Chronic fatigue, anaemia, stress, or overweight/obesity can induce symptoms reminiscent of hypothyroidism; excluding such conditions commonly resolves the issues presented by the patient, but may be difficult in practice for some. 23,25 A systematic review and meta-analysis of 58 studies of the associations between TSH levels, other thyroid hormones and symptoms of thyroid dysfunction found a weaker association between TSH and clinical findings compared with other thyroid hormones, especially FT4.…”

“…23,25 Chronic fatigue, anaemia, stress, or overweight/obesity can induce symptoms reminiscent of hypothyroidism; excluding such conditions commonly resolves the issues presented by the patient, but may be difficult in practice for some. 23,25 A systematic review and meta-analysis of 58 studies of the associations between TSH levels, other thyroid hormones and symptoms of thyroid dysfunction found a weaker association between TSH and clinical findings compared with other thyroid hormones, especially FT4. 26 In addition, thyroid hormone homeostasis varies between individuals: a given patient may have an individual "set point" for thyroid hormones, which reflects their optimal thyroid balance, even if levels of some thyroid hormones fall outside the reference range defined by measurements in a cohort believed to have "normal" thyroid function.…”