Is Pituitary Thyrotropin an Adequate Measure Of Thyroid Hormone-Controlled Homeostasis During Thyroxine Treatment?

R Hoermann, Department of Nuclear Medicine, Klinikum Luedenscheid, Lüdenscheid, Germany.
European Journal of Endocrinology (Impact Factor: 4.07). 02/2013; 168(2):271-80. DOI: 10.1530/EJE-12-0819
Source: PubMed


In recognition of its primary role in pituitary-thyroid feedback, TSH determination has become a key parameter for clinical decision-making. This study examines the value of TSH as a measure of thyroid hormone homoeostasis under thyroxine (T(4)) therapy.

Design and methods:
We have examined the interrelationships between free triiodothyronine (FT(3)), free T(4) (FT(4)) and pituitary TSH by means of i) a retrospective analysis of a large clinical sample comprising 1994 patients either untreated or on varying doses of l-T(4) and ii) independent mathematical simulation applying a model of thyroid homoeostasis, together with a sensitivity analysis.

Over a euthyroid to mildly hyperthyroid functional range, we found markedly different correlation slopes of log TSH vs FT(3) and FT(4) between untreated patients and l-T(4) groups. Total deiodinase activity (G(D)) was positively correlated with TSH in untreated subjects. However, G(D) was significantly altered and the correlation was lost under increasing l-T(4) doses. Ninety-five per cent confidence intervals for FT(3) and FT(4), when assessed in defined TSH concentration bands, differed significantly for l-T(4)-treated compared with untreated patients. Higher doses were often needed to restore FT(3) levels within its reference range. Sensitivity analysis revealed the influence of various structural parameters on pituitary TSH secretion including an important role of pituitary deiodinase type 2.

The data reveal disjoints between FT(4)-TSH feedback and T(3) production that persist even when sufficient T(4) apparently restores euthyroidism. T(4) treatment displays a compensatory adaptation but does not completely re-enact normal euthyroid physiology. This invites a study of the clinical consequences of this disparity.

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    • "TSH has been considered as a highly sensitive measure of the thyroid dysfunction, but current issues challenge inverse log TSH-FT4 relationship and demonstrate complex nature of the TSH response to changes in FT4 [45]. In addition, population-based studies of euthyroid subjects have reported wide variations of FT4/TSH between individuals in contrast to narrow intraindividual variation of TSH, suggesting individual setpoint of the HPT axis, inherited as a genetic trait [46]. "
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    ABSTRACT: We investigated whether thyroid function could identify obesity phenotype in euthyroid subjects. A cross-sectional analysis was performed among nondiabetic, euthyroid subjects. We stratified subjects into four groups by BMI and insulin resistance (IR). Of 6241 subjects, 33.8% were overweight or obese (OW/OB) and 66.2% were normal weight (NW). Free thyroxine (FT4) levels were negatively associated with body mass index, waist circumference, triglyceride, c-reactive protein, and HOMA-IR and positively with high-density lipoprotein cholesterol in both genders. In multivariate regression analysis, FT4 level, a continuous measurement, was negatively correlated with HOMA-IR (β = -0.155, P < 0.001 in men; β = -0.175, P < 0.001 in women). After adjustment for age, sex, metabolic, and life style factors, subjects in the lowest FT4 quartile had an odds ratio (OR) for IR of 1.99 (95% confidence interval 1.61-2.46), as compared to those in the highest quartile. The association between low FT4 and IR remained significant in both NW and OW/OB subgroups. In conclusion, low normal FT4 levels were independently related to IR in NW and OW/OB euthyroid subjects. Further studies are needed to investigate the mechanisms by which low FT4 levels are linked to high IR in euthyroid ranges.
    Full-text · Article · Apr 2014 · International Journal of Endocrinology

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    ABSTRACT: High-dose thyroid hormone replacement has been recommended for treatment of myxedema coma (MC) while questions of safety of the therapy and of efficacy of low-dose thyroid hormone replacement have not been systematically addressed. We treated 8 patients with MC in a period of 18 years, the first 3 with high-dose intravenous injections of levotriiodothyronine (LT3) and the other 5 patients with a smaller amount of either LT3 or levothyroxine (LT4). Two of the first 3 patients died of pneumonia and the other 5 recovered despite pulmonary abnormalities at the outset. To find factors associated with fatal outcome after treatment, the MEDLINE database was searched for MC cases with data of thyroid hormone replacement and outcome within 1 month of therapy. Clinical data for our 5 patients and 82 cases from the MEDLINE search were pooled and factors associated with mortality were sought among age, gender, presence of cardiac or pulmonary complications, and doses of thyroid hormone by multiple logistic regression analysis. It revealed that greater age, cardiac complications, and high-dose thyroid hormone replacement (LT4 > or = 500 microg/d or LT3 > or = 75 microg/d) were significantly associated with a fatal outcome within 1 month of treatment. Elderly MC patients can be treated with low-dose hormone replacement. A bolus of 500 microg LT4, especially by mouth or via nasogastric tube, appears to be tolerated by younger patients (< 55 years) without cardiac complication. The conclusion remains to be confirmed in more patients.
    Preview · Article · Jan 2000 · Thyroid
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Questions & Answers about this publication

  • Johannes W. Dietrich added an answer in Cardiac Arrhythmias:
    What is the best way to clinically assess thyroid function?

    There is a tendency among doctors to assess thyroid function, i.e. hypo- and hyperthyroidism simply by measuring TSH. It is argued that clinical scores are complicated, difficult to obtain and imprecise. Notwithstanding the ongoing discussion of the "true" reference range for TSH, mere evaluation of a laboratory value will falsly classify 3% of euthyroid persons as either hypo- or hyperthyroid, as their TSH values will be outside the 97% normal range - assuming Gaussian distribution. On the other hand, patients report better quality of life when they are "on the edge of hyperthyroidism" although this - subclinical hyperthyroidism - is a known risk factor for cardiac arrhythmias and osteoporosis. Is there a simple way to assess thyroid function, maybe with questions about heat and cold intolerance, being tired or nervous and loss or gain of weight? Has some such score been evaluated in a study of long-term health effects of thyroid function?

    Johannes W. Dietrich

    Yesterday the Journal of Clinical Investigation published a new paper by the groups of Balazs Gereben and Antonio Bianco. Among other interesting things they demonstrated that the location of the set point is modified by ubiquitination of central type 2 deiodinase. These findings confirm earlier in silico predictions with a nonlinear model of thyroid homeostasis [Hoermann et al. 2013].

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