SUMMARY of Midgley et al, 2015
Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency. Endocrine Connections, 4(4), 196–205. LINK: https://ec.bioscientifica.com/view/journals/ec/4/4/196.xml
“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 (17, 18).
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 (19, 20, 21).”
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 (22).
- 353 patients (280 women)
- Average age 56
Patients were analyzed in three separate groups according to the cause of hypothyroidism.
- 27% Autoimmune thyroiditis
- 32% Benign thyroid disease after surgery
- 41% Thyroid carcinoma
TSH and Free T4 were both within reference range, except for suppressed TSH in carcinoma patients.
- No interfering drugs or illnesses
Patients were divided into three categories for each type of hypothyroidism, based on their ability to convert T4 into T3: Good converters, Intermediate converters, Poor converters, with cutoffs determined by a previous study.
- Dissociation between FT3 and FT4
- disjoint between TSH and FT3
- Inverse association between TSH and FT3
The poor converters reached significantly higher FT4 concentrations in the circulation than intermediate or good converters but, at the same time, showed significantly lower absolute FT3 levels compared to the other two groups (Fig. 2).
[Figures reproduced with permission: Creative Commons License By-NC 4.0]
Figure 2: FT3 (A), FT4 (B) and TSH (C) levels in l-T4-treated patients stratified by disease and conversion efficiency. The disease entities were closely associated with categories of the thyroid volume (see Table 1 and text). The red box refers to poor converters (calculated deiodinase activity <23 nmol/s), green to intermediate converters (deiodinase activity 23–29 nmol/s) and blue to good converters (deiodinase activity >29 nmol/s). Remarkably, absolute FT3 concentrations were lowest in the poor converter group in all disease categories, while FT4 levels were highest in the poor converters. Wilcoxon test, revealed significant differences compared to each first group; *P<0.05, **P<0.001. AIT, autoimmune thyroiditis; goitre, goitre post surgery for benign nodular thyroid disease.
What factors altered conversion efficiency?
- Thyroid volume was significantly associated with T4-T3 conversion efficiency
- Men were better converters than women
- L-T4 dosage and Free T4 levels affected conversion in unexpected ways
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.
How can this be explained?
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 [T4] substrate itself and/or reverse T3 (rT3) on deiodinase type 2 activity (27).
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 (42, 43, 44, 45).
Compared to untreated subjects, deiodinase activity and conversion efficiency tend to be diminished in L-T4 treatment (20, 22).
The problem of the FT3 – TSH Disjoint
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.
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 (20, 22, 29, 30, 40, 41).
Overall, patients differ widely in the degree of the conversion impairment they suffer.
In two studies, 15% of athyreotic patients could not even raise their FT3 above
the lower reference limit on L-T4 (19, 20).
We speculate that L-T4-induced conversion inefficiency could prevent some vulnerable subjects from reaching true tissue normality on T4 monotherapy alone.
Implications for thyroid therapy
- The T3–T4 ratio is an important determinant of L-T4 dose requirements and the biochemical response to treatment.
- in view of a T4-related FT3–TSH disjoint, FT3 measurement should be adopted as an additional treatment target.
- 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.