Increased fT4 concentrations in patients using levothyroxine without complete suppression of TSH
Authors: Heleen I Jansen et al . 2023 ec.bioscientifica.com/view/...
I found this study ....it's not from endocrinologists , it was done by Lab researchers in the Netherlands ,
They were looking for reasons for discordant fT4 / TSH test results (over range fT4 without supressed TSH). they had originally wondered if their new fT4 assay (blood test machine) was the problem, but it wasn't.
I think we can all agree they come to a thoughtful and intelligent conclusion, based on up to date knowledge ........ and in their conclusion they make several good suggestions to improve testing for thyroid patients.
"....There may be various causes contributing to this phenomenon in L-T4 users. Timing of blood withdrawal following L-T4 intake can lead to high fT4 concentrations without (complete) TSH suppression. Hypothyroid patients are mainly treated with L-T4 and the effect of treatment is monitored by measuring serum TSH, sometimes accompanied by fT4. Hypothyroid patients are advised to take a single daily dose of L-T4 orally in a fasting state. L-T4 administration in the morning or at bedtime is considered equally effective as long as L-T4 is taken on an empty stomach to ensure optimal uptake (14, 15). In contrast to fT4, no direct alterations of TSH and T3 have been reported directly after L-T4 ingestion (4, 5, 6, 7, 8). An fT4 course as Fig. 2 presents was found in patients taking L-T4 in the morning before breakfast, and one would also expect an increase in fT4 levels during the night when L-T4 is taken at bedtime (16). However, literature on extensive follow-up of fT4 and TSH levels following L-T4 intake in the morning compared to bedtime is lacking. Ain et al. (7) as well as Hoermann et al. (17) specifically emphasized that fT4 concentrations in L-T4 users were influenced by the time of day, meaning the time interval between L-T4 intake and blood sampling should be considered in the interpretation of fT4 values. In line with this advice, the European Thyroid Association guideline on treating central hypothyroidism advises blood withdrawal for monitoring treatment to be performed before L-T4 intake or at least 4 h after L-T4 intake (18), but other international guidelines do not yet (19) To the best of our knowledge, only Conte et al. (20) investigated if timing of blood sampling affected the evaluation of (morning) L-T4 treatment in patients with differentiated thyroid carcinoma and showed an increase in fT4 concentration in the afternoon compared to the morning without TSH deviation in this group. The observed increase (2.8 pmol/L) might not always be determined clinically relevant because treatment decisions are mainly based on changes in TSH. However, such fluctuations in fT4 concentrations may be relevant for evaluating treatment effects if TSH cannot be used as a marker to monitor thyroidal status (e.g. in central hypothyroidism).
Furthermore, a higher fT4/fT3 ratio was seen in patients using L-T4 compared to healthy controls (12, 21, 22). Hypothyroid patients receive L-T4 supplementation which replaces T4 only and thus these patients partially lack the active thyroid hormone triiodothyronine (T3) derived from the thyroid gland. This suggests a need for increased conversion of T4 into T3 in the peripheral tissues to reach adequate tissue T3 concentrations (21), resulting in the need for a higher L-T4 dosage to obtain a normal, or even somewhat lower, concentration of T3 (22, 23). Moreover, TSH is more sensitive to changes in T3 than in T4, clarifying the lack of negative pituitary feedback to increased fT4 concentrations leading to not (completely) suppressed TSH. This phenomenon may be more prominent in patient groups that are characterized by an even greater deficit of endogenous T3 production (e.g. athyroid patients). Even though in athyroid patients some T3 is still produced by deiodinases in several tissues, previous literature showed an outspoken dissociation between fT4 and fT3 concentrations in this group where even a higher L-T4 dosage did not lead to adequate fT3 concentrations (24). Thus, the adapted peripheral conversion of T4 into T3 in L-T4 users leads to an increased fT4 concentration combined with a not (completely) suppressed TSH, which is reflected in a higher fT4/fT3 ratio.
In conclusion, the observed fT4 concentrations above the ULN together with not (completely) suppressed TSH were not caused by incorrect reference intervals or analytical problems but mainly related to L-T4 use. Most likely, a combination of timing of blood withdrawal and the timing of L-T4 intake causes this phenomenon. The retrospective design of our study did not allow us to investigate this further in our cohorts. Physicians and laboratory specialists should be aware of the importance of timing of blood withdrawal and the timing of L-T4 intake to avoid questioning the assay’s performance or, worse, unnecessarily adapting L-T4 dose in patients. The clinical implications of discrepant TSH and fT4 concentrations may differ among specific L-T4 treated groups, as treatment and follow-up approaches are different. One could argue that TSH measurements suffice during treatment follow-up, but measuring TSH alone in L-T4 users has its limitations as well (25). These findings may argue for the application of an integrative approach by adding the measurement of fT3 or the fT4/fT3 ratio as a more reliable reflection of thyroid hormone status in L-T4 users considering the adapted peripheral conversion of T4 into T3 in L-T4 users. Furthermore, specific reference intervals or altered target values of fT4 for L-T4 users could be determined and used, ideally specified for different specific L-T4 treated groups (e.g. Hashimoto’s hypothyroidism, central hypothyroidism, athyroid patients). Last and potentially easiest, it can be advised to draw blood at fixed time points to ensure proper result comparisons over time."
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Then ..... some American endo's read it ...and write an article on it.
.... below is their summary , it's written by the American Thyroid Association ('for the public' ), and they somehow manage to translate the study's conclusion into this :
thyroid.org/patient-thyroid... (Summaries for the Public from recent articles in Clinical Thyroidology)
"WHAT ARE THE IMPLICATIONS OF THIS STUDY?
These data show that 2-4% of individuals will have an increased FT4 and normal TSH and that ~80% of these results will be obtained in patients currently taking levothyroxine. Measuring just TSH for the monitoring of thyroid levels in patients taking levothyroxine may be more useful of the TSH level returns in the normal range. However, if the TSH returns abnormal (either high or low), a FT4 level can be helpful".
..... which seems to be saying: 'if high fT4 is worrying you (when TSH is in range) .... stop testing it... problem solved'. .............. (well that's my translation ...lol)
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So that's all right then ... (not)
eg .
I recently got some unexpected results:
TSH 2.65
fT4 15.7 [7.9-14] 128% testing
fT3 4 [3.1-6.8] 24%
which was a bit of a surprise, given that i have an 18 yr history of TSH between 0.05 and 0.2, with fT3 between 40 -60% ....
(taking consistent dose /test protocol and last dose timing etc are all consistent will my previous tests, so before anyone asks ~ time of last dose / non-compliance is not an explanation for this particular set of discordant results ... so presumably it is because something has lowered my conversion of T4 to T3)
and so knowing what i know about higher fT4 levels and cancer cell proliferation risks / 'too high' fT4 levels reducing deiodinase conversion to T3. etc etc ....... i thought i should perhaps take some action, or at least take some notice .... but no ! it seems there is a much easier solution..... i can just ignore the high fT4 problem by testing TSH on it's own in future ... problem solved. Thanks ATA
(not)
Quotes that might help your case
