Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?

Hoermann, Rudolf; Midgley, J. E. M.; Larisch, Rolf; Dietrich, Johannes W.

doi:10.1530/eje-12-0819

Cited by 50 publications

(71 citation statements)

References 46 publications

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“…As a consequence, although dose escalation may help some patients who maintained a sufficiently efficient thyroid hormone conversion to raise their FT 3 for euthyroidism and well-being, the strategy may not be invariably successful in all patients. In two studies, w15% of athyreotic patients could not even raise their FT 3 above the lower reference limit on L-T 4 (19,20). Another controlled follow-up study after hemithyroidectomy for benign euthyroid goitre suggests that this deficiency may have unwanted clinical consequences.…”

Section: Discussionmentioning

confidence: 99%

“…As useful as these algorithms may be for average predictions and initial guidance in the general population, they do not take into account individual variations in the response to L-T 4 , such as conversion efficiency. Dosing strategies solely based on a TSH definition of euthyroidism neglect the important role of FT 3 , which has recently emerged as an equally significant parameter in defining thyroid physiology (20,22,29,30,40,41). Central and peripheral regulatory mechanisms do not constitute divided levels of control, as has previously been assumed.…”

Section: Discussionmentioning

confidence: 99%

“…Compared to untreated subjects, deiodinase activity and conversion efficiency tend to be diminished in L-T 4 treatment (20,22). However, individual pre-treatment measurements were not available for comparison.…”

Section: Discussionmentioning

confidence: 99%

“…as previously described (20,21,24). Although the two measures are closely related in the linear part of the substrate relationship defined by Michaelis-Menten kinetics, only the more complex formula (G D ) accounts for the saturation kinetics of the enzyme.…”

Section: Ft 3 -Ft 4 Ratio and Calculated Deiodinase Activitymentioning

confidence: 94%

“…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-T 4 -treated patients (19,20,21). 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 (22).…”

Section: Introductionmentioning

confidence: 99%

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Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Midgley¹,

Larisch²,

Dietrich³

et al. 2015

Endocrine Connections

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Several influences modulate biochemical responses to a weight-adjusted levothyroxine (L-T 4 ) replacement dose. We conducted a secondary analysis of the relationship of L-T 4 dose to TSH and free T 3 (FT 3 ), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state L-T 4 replacement for autoimmune thyroiditis or after surgery for malignant or benign thyroid disease. Peripheral deiodinase activity was calculated as a measure of T 4 -T 3 conversion efficiency. In euthyroid subjects, the median L-T 4 dose was 1.3 mg/kg per day (interquartile range (IQR) 0.94,1.60). The dose was independently associated with gender, age, aetiology and deiodinase activity (all P!0.001). Comparable FT 3 levels required higher L-T 4 doses in the carcinoma group (nZ143), even after adjusting for different TSH levels. Euthyroid athyreotic thyroid carcinoma patients (nZ50) received 1.57 mg/kg per day L-T 4 (IQR 1.40, 1.69), compared to 1.19 mg/kg per day (0.85,1.47) in autoimmune thyroiditis (P!0.01, nZ76) and 1.08 mg/kg per day (0.82, 1.44) in patients operated on for benign disease (P! 0.01, nZ80). Stratifying patients by deiodinase activity categories of !23, 23-29 and O29 nmol/s revealed an increasing FT 3 -FT 4 dissociation; the poorest converters showed the lowest FT 3 levels in spite of the highest dose and circulating FT 4 (P!0.001). An L-T 4 -related FT 3 -TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT 3 above the median level. These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to L-T 4 ; FT 3 measurement may be an additional treatment target; and L-T 4 dose escalation may have limited success to raise FT 3 appropriately in some cases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ft 3 -Ft 4 Ratio and Calculated Deiodinase Activitymentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Midgley¹,

Larisch²,

Dietrich³

et al. 2015

Endocrine Connections

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Nicotinamide phosphoribosyltransferase leukocyte overexpression in Graves’ opthalmopathy

et al. 2016

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To investigate the role of NAMPT/visfatin in euthyroid patients with Graves’ disease without (GD) and with Graves’ ophthalmopathy (GO), we analyzed NAMPT leukocyte expression and its serum concentration. This was a single-center, cross-sectional study with consecutive enrollment. In total, 149 patients diagnosed with Graves’ disease were enrolled in the study. We excluded subjects with hyper- or hypothyroidism, diabetes mellitus, other autoimmune disorders, active neoplastic disease, and infection. The control group was recruited among healthy volunteers adjusted for age, sex, and BMI with normal thyroid function and negative thyroid antibodies. Serum levels of visfatin, TSH, FT4, FT3, antibodies against TSH receptor (TRAb), antithyroperoxidase antibodies, antithyroglobulin antibodies, fasting glucose, and insulin were measured. NAMPT mRNA leukocyte expression was assessed using RT-qPCR. NAMPT/visfatin serum concentration was higher in GD (n = 44) and GO (n = 49) patients than in the control group (n = 40) (p = 0.0275). NAMPT leukocyte expression was higher in patients with GO (n = 30) than in GD patients (n = 27) and the control group (n = 29) (p < 0.0001). Simple linear regression analysis revealed that NAMPT/visfatin serum concentration was significantly associated with GD (β = 1.5723; p = 0.021). When NAMPT leukocyte expression was used as a dependent variable, simple regression analysis found association with TRAb, fasting insulin level, HOMA-IR, GD, and GO. In the stepwise multiple regression analysis, we confirmed the association between higher serum NAMPT/visfatin level and GD (coefficient = 1.5723; p = 0.0212), and between NAMPT leukocyte expression and GO (coefficient = 2.4619; p = 0.0001) and TRAb (coefficient = 0.08742; p = 0.006). Increased NAMPT leukocyte expression in patients with GO might suggest a presently undefined role in the pathogenesis of GO.

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T4 + T3 combination therapy: any progress?

Wiersinga

2019

Endocrine

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Guidelines on T4 + T3 combination therapy were published in 2012. This review investigates whether the issue is better understood 7 years later. Dissatisfaction with the outcome of T4 monotherapy remains high. Persistent symptoms consist mostly of fatigue, weight gain, problems with memory and thinking and mood disturbances. T4 monotherapy is associated with low serum T3 levels, which often require TSH-suppressive doses of L-T4 for normalization. Peripheral tissue thyroid function tests during T4 treatment indicate mild hyperthyroidism at TSH < 0.03 mU/L and mild hypothyroidism at TSH 0.3–5.0 mU/L; tissues are closest to euthyroidism at TSH 0.03–0.3 mU/L. This is explained by the finding that whereas T4 is usually ubiquinated and targeted for proteasomal degradation, hypothalamic T4 is rather stable and less sensitive to ubiquination. A normal serum TSH consequently does not necessarily indicate a euthyroid state. Persistent symptoms in L-T4 treated patients despite a normal serum TSH remain incompletely understood. One hypothesis is that a SNP (Thr92Ala) in DIO2 (required for local production of T3 out of T4) interferes with its kinetics and/or action, resulting in a local hypothyroid state in the brain. Effective treatment of persistent symptoms has not yet realized. One may try T4 + T3 combination treatment in selected patients as an experimental n = 1 study. The 2012 ETA guidelines are still valid for this purpose. More well-designed randomized clinical trials in selected patients are key in order to make progress. In the meantime the whole issue has become rather complicated by commercial and political overtones, as evident from skyrocketing prices of T3 tablets, aggressive pressure groups and motions in the House of Lords.

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Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment?

Cited by 50 publications

References 46 publications

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

Nicotinamide phosphoribosyltransferase leukocyte overexpression in Graves’ opthalmopathy

T4 + T3 combination therapy: any progress?

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