Thyroid hormone conversion affects hypothyroid treatment
Levothyroxine (l-T4, the synthetic form of thyroxine/T4) is the standard agent used for hormone replacement therapy in the treatment of hypothyroid. The relatively inactive thyoxine must be converted outside the thyroid gland into the active form of thyroid hormone triiodothyronine (T3). A study recently published in the journal Endocrine Connections reminds clinicians that all too often patients are not adequately supported—and testing only TSH and T4 is insufficient for thyroid case management—because the conversion of T4 to the active T3 is impaired. The authors state regarding thyroid hormone replacement:
"This is mainly done by administration of synthetic levothyroxine (l-T4)...However, this does not accurately reflect the natural direct secretion pattern of both thyroid hormones triiodothyronine (T3) and thyroxine (T4) by the thyroid gland."
Measuring just TSH is not enough
Too many factors can influence TSH levels to solely depend on it as a biomarker for treatment of hypothyroid.
"Although TSH measurement has dominated procedural management of thyroid replacement by its apparent ease and good standardisation, a disturbingly high proportion of patients remains unsatisfied with the treatment they receive. This has prompted some authors including our group to question the validity of relying on the TSH level as the sole measure of dose adequacy in l-T4-treated patients. We have shown that the homeostatic equilibria between TSH and peripheral thyroid hormones are modulated by various influences such as age, body mass and the treatment modality itself. As a controlling element, the effective TSH level derived in a healthy normal population cannot necessarily be inferred to be equally optimal for a given patient on l-T4 medication, because the constitutive equilibria between TSH and thyroid hormones, especially FT3, differ in health and disease."
The authors examined the relationship of the dose of levothyroxine with clinical and biochemical outcomes such as the levels of TSH, free T4 (FT4) and free T3 (FT3), especially the interaction between TSH and the functionally paramount FT3 target. They also analyzed the influences of gender, age, disease category and the efficiency of T3 conversion from T4 with calculated deiodinase activity.
Higher levels of T4 can be associated with even lower T3
Free T4 was not reliable in predicting the level of free T3 in treating hypothyroid with levothyroxine.
"In l-T4 treatment, equilibria typical of the healthy state were found not to be invariant, but profoundly altered...We found that a poor converter status was associated with a higher l-T4 dose and higher serum FT4 levels but still lower absolute FT3 concentrations, compared to the more efficient converters. This paradoxically relates the higher T4 supply to a worsened rather than improved absolute FT3 level. This is not to say that an increasing dose will not raise on average the FT3 but that the dose response varies widely among individuals, and conversion inefficiency in some patients may outweigh the dose effect in terms of achievable absolute FT3 concentrations."
Higher doses of levothyroxine can hinder conversion to T3
Trying to improve hypothyroid functional status by just increasing l-T4 dosage can backfire:
"A high l-T4 dose may not invariably remedy T3 deficiency owing to T4-induced conversion inefficiency but could actually hinder its attainment through the inhibitory actions of the substrate itself and/or reverse T3 (rT3) on deiodinase type 2 activity...escalating only the l-T4 dose fails to normalize serum T3 in the rat, and as a result, irrespective of local variations by type of deiodinase, all organs examined such as the brain, liver and skeletal muscle were hypothyroid at the tissue level in the presence of a normal serum TSH...The lack of TSH stimulation and absence or functional deficiency of the thyroid gland may also impair T4–T3 conversion...Another important consideration is that, just as FT4 and FT3 dissociate under l-T4 therapy, so do TSH and FT3."
Even when TSH is suppressed by l-T4 treatment the FT3 can remain at hypothyroid levels:
"While a high proportion of patients was able to achieve a target of a suppressed TSH below the lower reference limits or a TSH value <1 mU/l in autoimmune thyroiditis, their FT3 levels at the same time frequently remained below the median FT3 level found in normal subjects. The situation differs from conditions in which l-T4 absorption may be impaired and, as a consequence, elevated TSH levels persist. Thus, not even an l-T4 dose in which TSH is fully suppressed and FT4 by far exceeds its upper reference limit can guarantee above average FT3 levels in these patients, indicating an FT3–TSH disjoint."
Unwanted clinical consequences can result even though lowered remains within the reference range:
"As a consequence, although dose escalation may help some patients who maintained a sufficiently efficient thyroid hormone conversion to raise their FT3 for euthyroidism and well-being, the strategy may not be invariably successful in all patients. In two studies, ∼15% of athyreotic patients could not even raise their FT3 above the lower reference limit on l-T4. Another controlled follow-up study after hemithyroidectomy for benign euthyroid goitre suggests that this deficiency may have unwanted clinical consequences. In this study, weight gain after 2 years in association with a lowered thyroid function within the laboratory reference range was interpreted as a clinical manifestation of a permanently decreased metabolic rate."
Clinicians must not ignore the importance of FT3
Measuring only TSH or TSH and T4 is inadequate for evaluation of hypothyroid:
"Dosing strategies solely based on a TSH definition of euthyroidism neglect the important role of FT3, which has recently emerged as an equally significant parameter in defining thyroid physiology. Central and peripheral regulatory mechanisms do not constitute divided levels of control, as has previously been assumed. Rather they are integrated via feed-forward control of deiodinase activity by TSH and operate jointly to maintain T3 homeostasis as an overarching goal."
Thus T4 monotherapy itself can make things worse:
"While acknowledging the role of genetically determined differences in deiodinase activity affecting conversion rates, the poor converter status described here appears to emerge mainly as a consequence of the T4 monotherapy itself, induced by the mechanisms discussed above. Compared to untreated subjects, deiodinase activity and conversion efficiency tend to be diminished in l-T4 treatment."
Treatment may require T3 replacement
As usual, therapy must be individualized:
"Overall, patients differ widely in the degree of the conversion impairment they suffer. This, in turn, may influence their dose requirements of l-T4 and, at a comparable weight-adjusted l-T4 dose, their levels of TSH suppression and circulating FT3 concentrations."
Regarding combinations of T3 and T4:
"We speculate that l-T4-induced conversion inefficiency could prevent some vulnerable subjects from reaching true tissue normality on T4 monotherapy alone. Those were not analysed separately in the numerous earlier T3/T4 trials and could be possible candidates for a combined T3/T4 treatment option, as recognized by some authors and the guidelines of the European Thyroid Association."
Clinicians who participate in case management of hypothyroid should bear in mind the authors' conclusions:
"The findings of the present study have several clinical implications. First, they recognize thyroid hormone conversion efficiency, as defined by the calculated global deiodinase activity or more simply the T3–T4 ratio, is an important determinant of l-T4 dose requirements and the biochemical response to treatment. Second, in view of a T4-related FT3–TSH disjoint, FT3 measurement should be adopted as an additional treatment target. Third, in cases where an FT3–FT4 dissociation becomes increasingly apparent following dose escalation of l-T4, an alternate treatment modality, possibly T3/T4 combination therapy, should be considered, but further randomized controlled trials are required to assess the benefit versus risk in this particular group."