The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome

Dietrich, Johannes W.; Stachon, Axel; Antic, Biljana; Klein, Harald; Hering, S.

doi:10.1186/1472-6823-8-13

Cited by 36 publications

(45 citation statements)

References 29 publications

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“…Central T 3 rises with increasing GD 2 activity, thereby suppressing TSH and, as a consequence, circulating FT 3 and FT 4 levels decline. G D1 , maximum activity of type I deiodinase; K M1 , dissociation constant of 5 0 -deiodinase I; G D2 , maximum activity of type II deiodinase; K M2 , dissociation constant of 5 0 -deiodinase II; G T , secretory capacity of thyroid gland; D T , damping constant (EC 50 ) of TSH at the thyroid gland; G H , secretory capacity of the pituitary; D H , damping constant (EC 50 ) of TRH at the pituitary; S S , brake constant of TSH ultrashort feedback; D S , EC 50 for TSH at the pituitary; GR, maximum gain of TRb receptors; D R , EC 50 for central T 3 , beta S , clearance exponent for TSH; beta S2 , clearance exponent for central TSH; beta T , clearance exponent for T 4 ; beta 31 , clearance exponent for T 3P ; beta 32 , clearance exponent for central T 3 ; L S , brake constant (adopted from Dietrich et al (15,17)). Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-12-0819.…”

Section: Discussionmentioning

confidence: 99%

“…from equilibrium levels for FT 4 and FT 3 and from constant parameters for kinetics, plasma proteins and dissociation constants as previously defined and described (17).…”

Section: Calculations Models and Statistical Methodsmentioning

confidence: 99%

“…It allows mapping of the physiological and biochemical interplay to the various parameters involved. With this simulative approach, sensitivity analysis was performed to study the relationship between certain structural parameters such as type 2 deiodinase (D 2 ) and thyroid parameters (17). The mathematical equation used for empirical curve fitting was as follows: TSHZs/(1CL S !FT 4 ), with s referring to maximum secretory capacity and L S to the brake constant of non-competitive inhibition at the pituitary site.…”

Section: Calculations Models and Statistical Methodsmentioning

confidence: 99%

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

Hoermann

Midgley²,

Larisch

et al. 2013

European Journal of Endocrinology

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Objective: 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. Results: 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. Conclusion: 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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Section: Discussionmentioning

confidence: 99%

“…from equilibrium levels for FT 4 and FT 3 and from constant parameters for kinetics, plasma proteins and dissociation constants as previously defined and described (17).…”

Section: Calculations Models and Statistical Methodsmentioning

confidence: 99%

Section: Calculations Models and Statistical Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Hoermann

Midgley²,

Larisch

et al. 2013

European Journal of Endocrinology

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“…The SPINA parameters have been validated in a number of studies in different populations comprising together more than 10,000 subjects [6,7,8,9,10,11]. They can be calculated with free open source software (SPINA Thyr 4.0), available from sourceforge.net (RRID:SCR_014352, http://spina.sf.net).…”

Section: Methodsmentioning

confidence: 99%

Relational Stability of Thyroid Hormones in Euthyroid Subjects and Patients with Autoimmune Thyroid Disease

Hoermann¹,

Midgley²,

Larisch³

et al. 2016

Eur Thyroid J

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Background/Aim: Operating far from its equilibrium resting point, the thyroid gland requires stimulation via feedback-controlled pituitary thyrotropin (TSH) secretion to maintain adequate hormone supply. We explored and defined variations in the expression of control mechanisms and physiological responses across the euthyroid reference range. Methods: We analyzed the relational equilibria between thyroid parameters defining thyroid production and thyroid conversion in a group of 271 thyroid-healthy subjects and 86 untreated patients with thyroid autoimmune disease. Results: In the euthyroid controls, the FT₃-FT₄ (free triiodothyronine-free thyroxine) ratio was strongly associated with the FT₄-TSH ratio (tau = -0.22, p < 0.001, even after correcting for spurious correlation), linking T₄ to T₃ conversion with TSH-standardized T₄ production. Using a homeostatic model, we estimated both global deiodinase activity and maximum thyroid capacity. Both parameters were nonlinearly and inversely associated, trending in opposite directions across the euthyroid reference range. Within the panel of controls, the subgroup with a relatively lower thyroid capacity (<2.5 pmol/s) displayed lower FT₄ levels, but maintained FT₃ at the same concentrations as patients with higher functional and anatomical capacity. The relationships were preserved when extended to the subclinical range in the diseased sample. Conclusion: The euthyroid panel does not follow a homogeneous pattern to produce random variation among thyroid hormones and TSH, but forms a heterogeneous group that progressively displays distinctly different levels of homeostatic control across the euthyroid range. This suggests a concept of relational stability with implications for definition of euthyroidism and disease classification.

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“…Secondary outcome measures were concentrations of other hormones involved in thyroid homeostasis (total and free T 4 , TSH), total T 3 and nonclassical TH [3,5-diiodothyronine (3,5-T 2 ), 3,3′,5′-triiodothyronine (reverse, rT 3 ) and 3-iodothyronamine (3-T 1 AM)]. In order to get exploratory information on pathophysiological processes, derived parameters of thyroid homeostasis were calculated, including thyroid's secretory capacity (SPINA-GT), total deiodinase activity (SPINA-GD), FT 3 /rT 3 , 3,5-T 2 /FT 3 and 3,5-T 2 /rT 3 ratios [3,28,29,30,31,32] (see online suppl. methods for a detailed description; see www.karger.com/doi/10.1159/000381543 for all online suppl.…”

Section: Methodsmentioning

confidence: 99%

Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling

Dietrich¹,

Müller²,

Schiedat

et al. 2015

Eur Thyroid J

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Background: Although hyperthyroidism predisposes to atrial fibrillation, previous trials have suggested decreased triiodothyronine (T₃) concentrations to be associated with postoperative atrial fibrillation (POAF). Therapy with thyroid hormones (TH), however, did not reduce the risk of POAF. This study reevaluates the relation between thyroid hormone status, atrial electromechanical function and POAF. Methods: Thirty-nine patients with sinus rhythm and no history of atrial fibrillation or thyroid disease undergoing cardiac surgery were prospectively enrolled. Serum concentrations of thyrotropin, free (F) and total (T) thyroxine (T₄) and T₃, reverse (r)T₃, 3-iodothyronamine (3-T₁AM) and 3,5-diiodothyronine (3,5-T₂) were measured preoperatively, complemented by evaluation of echocardiographic and electrophysiological parameters of cardiac function. Holter-ECG and telemetry were used to screen for POAF for 10 days following cardiac surgery. Results: Seven of 17 patients who developed POAF demonstrated nonthyroidal illness syndrome (NTIS; defined as low T₃ and/or low T₄ syndrome), compared to 2 of 22 (p < 0.05) patients who maintained sinus rhythm. In patients with POAF, serum FT₃ concentrations were significantly decreased, but still within their reference ranges. 3,5-T₂ concentrations directly correlated with rT₃ concentrations and inversely correlated with FT₃ concentrations. Furthermore, 3,5-T₂ concentrations were significantly elevated in patients with NTIS and in subjects who eventually developed POAF. In multivariable logistic regression FT₃, 3,5-T₂, total atrial conduction time, left atrial volume index and Fas ligand were independent predictors of POAF. Conclusion: This study confirms reduced FT₃ concentrations in patients with POAF and is the first to report on elevated 3,5-T₂ concentrations in cardiac NTIS. The pathogenesis of NTIS therefore seems to involve more differentiated allostatic mechanisms.

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The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome

Cited by 36 publications

References 29 publications

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

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

Relational Stability of Thyroid Hormones in Euthyroid Subjects and Patients with Autoimmune Thyroid Disease

Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling

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