Rudolf Hoermann1, John E M Midgley2, Rolf Larisch1 and Johannes W Dietrich3,4 1Department for Nuclear Medicine, Klinikum Lüdenscheid, Lüdenscheid, Germany, 2North Lakes Clinical, Ilkley, UK, 3Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, Germany, and 4Ruhr Center for Rare Diseases (CeSER), Ruhr University of Bochum and Witten/Herdecke University, Bochum, Germany

The hypothalamus-pituitary-thyroid feedback control is a dynamic, adaptive system. In situations of illness and deprivation of energy representing type 1 allostasis, the stress response operates to alter both its set point and peripheral transfer parameters. In contrast, type 2 allostatic load, typically effective in psychosocial stress, pregnancy, metabolic syndrome, and adaptation to cold, produces a nearly opposite phenotype of predictive plasticity. The non-thyroidal illness syndrome (NTIS) or thyroid allostasis in critical illness, tumors, uremia, and starvation (TACITUS), commonly observed in hospitalized patients, displays a historically well-studied pattern of allostatic thyroid response. This is characterized by decreased total and free thyroid hormone concentrations and varying levels of thyroid-stimulating hormone (TSH) ranging from decreased (in severe cases) to normal or even elevated (mainly in the recovery phase) TSH concentrations. An acute versus chronic stage (wasting syndrome) of TACITUS can be discerned. The two types differ in molecular mechanisms and prognosis. The acute adaptation of thyroid hormone metabolism to critical illness may prove beneficial to the organism, whereas the far more complex molecular alterations associated with chronic illness frequently lead to allostatic overload. The latter is associated with poor outcome, independently of the underlying disease. Adaptive responses of thyroid homeostasis extend to alterations in thyroid hormone concentrations during fetal life, periods of weight gain or loss, thermoregulation, physical exercise, and psychiatric diseases. The various forms of thyroid allostasis pose serious problems in differential diagnosis of thyroid disease. This review article provides an overview of physiological mechanisms as well as major diagnostic and therapeutic implications of thyroid allostasis under a variety of developmental and straining conditions.

Although technical problems of thyroid testing have largely been resolved by modern assay technology, biological variation remains a challenge. This applies to subclinical thyroid disease, non-thyroidal illness syndrome, and those 10% of hypothyroid patients, who report impaired quality of life, despite normal thyrotropin (TSH) concentrations under levothyroxine (L-T4) replacement. Among multiple explanations for this condition, inadequate treatment dosage and monotherapy with L-T4 in subjects with impaired deiodination have received major attention. Translation to clinical practice is difficult, however, since univariate reference ranges for TSH and thyroid hormones fail to deliver robust decision algorithms for therapeutic interventions in patients with more subtle thy-roid dysfunctions. Advances in mathematical and simulative modeling of pituitary–thyroid feedback control have improved our understanding of physiological mechanisms govern-ing the homeostatic behavior. From multiple cybernetic models developed since 1956, four examples have also been translated to applications in medical decision-making and clinical trials. Structure parameters representing fundamental properties of the processing structure include the calculated secretory capacity of the thyroid gland (SPINA-GT), sum activity of peripheral deiodinases (SPINA-GD) and Jostel’s TSH index for assessment of thyrotropic pituitary function, supplemented by a recently published algorithm for reconstructing the personal set point of thyroid homeostasis. In addition, a family of integrated models (University of California-Los Angeles platform) provides advanced methods for bioequivalence studies. This perspective article delivers an overview of current clinical research on the basis of mathematical thyroid models. In addition to a summary of large clinical trials, it provides previously unpublished results of validation studies based on simulation and clinical samples.

SummarySetting the reference range for thyrotropin (TSH) remains a matter of ongoing controversy. Patients, methods: We used an indirect method to determine the TSH reference range post hoc in a large sample. A total of 399 well characterised subjects showing no evidence of thyroid dysfunction were selected for definition of the TSH reference limits according to the method of Katayev et al. To this end, the cumulative frequency was plotted against the individual logarithmic TSH values. Reference limits were calculated by extrapolating the middle linear part of the regression line to obtain the cut-offs for the 95% confidence interval. We also examined biological variation in a sample of 65 subjects with repeat measurements to establish reference change values (RCVs). Results: Based on these, the reference interval obtained by the novel technique was in close agreement with the conventionally established limits, but differed significantly from earlier recommendations. Discussion: Following unverified recommendations could result in a portion of patients with subclinical thyroid dysfunctions being missed, an important consideration in a setting with a high prevalence of thyroid autonomy. Conclusion: Indirect post hoc verification of reference intervals from a large retrospective sample is a modern approach that gives plausible results. The method seems particularly useful to assess the adequacy and performance of reference limits reported or established by others in a particular setting. The present data should encourage re-evaluation of reference systems on a broader scale.

The objective of the study was to evaluate the roles of central and peripheral T3 regulation. In a prospective study involving 1796 patients, the equilibria between FT3 and TSH were compared in untreated and L-T4-treated patients with varying functional states, residual thyroid secretory capacities and magnitudes of TSH stimulation. T3 concentrations were stable over wide variations in TSH levels (from 0.2 to 7mU/l) and endogenous T4 production in untreated patients, but unbalanced in L-T4-treated athyreotic patients where T3 correlated with exogenous T4 supply. T3 stability was related to TSH-stimulated deiodinase activity by clinical observation, as predicted by theoretical modelling. Deiodinase activity in treated patients was reduced due to both diminished responsiveness to TSH and lack of thyroidal capacity. Deiodinase activity was increased in high thyroid volume, compared to lower volumes in euthyroid patients (<5ml, p<0.001). While deiodinase differed between euthyroid and subclinically hypothyroid patients in high volume, 26.7nmol/s (23.6, 29.2), n=214 vs. 28.9nmol/s (26.7, 31.5), n=20, p=0.02, it was equivalent between the 2 functional groups in low volume, 23.3nmol/s (21.3, 26.1), n=117 vs. 24.6nmol/s (22.2, 27.5), n=38, p=0.22. These findings suggest that the thyroid gland and peripheral tissues are integrated in the physiological process of T3 homeostasis in humans via a feed-forward TSH motif, which coordinates peripheral and central regulatory mechanisms. Regulatory and capacity deficiencies collectively impair T3 homeostasis in L-T4-treated patients.

The long-held concept of a proportional negative feedback control between the thyroid and pituitary glands requires reconsideration in the light of more recent studies. Homeostatic equilibria depend on dynamic inter-relationships between thyroid hormones and pituitary thyrotropin (TSH). They display a high degree of individuality, thyroid-state-related hierarchy, and adaptive conditionality. Molecular mechanisms involve multiple feedback loops on several levels of organization, different time scales, and varying conditions of their optimum operation, including a proposed feedforward motif. This supports the concept of a dampened response and multistep regulation, making the interactions between TSH, FT4, and FT3 situational and mathematically more complex. As a homeostatically integrated parameter, TSH becomes neither normatively fixed nor a precise marker of euthyroidism. This is exemplified by the therapeutic situation with L-thyroxine (\(\tiny {L}\)-T4) where TSH levels defined for optimum health may not apply equivalently during treatment. In particular, an FT3–FT4 dissociation, discernible FT3–TSH disjoint, and conversion inefficiency have been recognized in \(\tiny {L}\)-T4-treated athyreotic patients. In addition to regulating T4 production, TSH appears to play an essential role in maintaining T3 homeostasis by directly controlling deiodinase activity. While still allowing for tissue-specific variation, this questions the currently assumed independence of the local T3 supply. Rather it integrates peripheral and central elements into an overarching control system. On \(\tiny {L}\)-T4 treatment, altered equilibria have been shown to give rise to lower circulating FT3 concentrations in the presence of normal serum TSH. While data on T3 in tissues are largely lacking in humans, rodent models suggest that the disequilibria may reflect widespread T3 deficiencies at the tissue level in various organs. As a consequence, the use of TSH, valuable though it is in many situations, should be scaled back to a supporting role that is more representative of its conditional interplay with peripheral thyroid hormones. This reopens the debate on the measurement of free thyroid hormones and encourages the identification of suitable biomarkers. Homeostatic principles conjoin all thyroid parameters into an adaptive context, demanding a more flexible interpretation in the accurate diagnosis and treatment of thyroid dysfunction.

Advances in assay technology have promoted thyrotropin (TSH) measurements from participation in a multi-analyte assessment of thyroid function to a statistically defined screening parameter in its own right. While this approach has been successful in many ways, it has some grave limitations. This includes the basic question of what constitutes an agreed reference range and the fact that the population-based reference range by far exceeds the variation of the intraindividual set point. Both problems result in a potential misdiagnosis of normal and pathological thyroid function in a substantial proportion of patients. From a physiological perspective, TSH plays an integrated role in thyroid homeostasis. Few attempts have been made to adopt physiological insights into thyroid homeostasis for medical decision-making. Some emerging novel findings question the widely assumed log-linear TSH-FT 4 relationship over the entire thyroid function spectrum. This data favours more complex hierarchically structured models. With a better understanding of its role in thyroid homeostasis in thyroid health and disease, TSH can be revisited in the context of thyroid regulation. This, in turn, could help overcome some of the limitations arising from its isolated statistical use and offer new prospects towards a more personalised interpretation of thyroid test results. Recognition of the existence of the entity later described as thyroid-stimulating hormone (TSH) was first evident in the late 19th century [1]. In the late 1960s and early 70s, academic immunoassays were developed and though initially cumbersome in use and somewhat insensitive, were quickly adopted as a diagnostic tool chiefly for determination of the hypothyroid state. From the mid 1980s to 1990s, steady developments in both convenience and sensitivity have so refined TSH assays that the concentrations of the hormone in subjects with normal thyroid function or with thyroid diseases are now readily quantifiable [2]. With the introduction of the third generation of commercial TSH assays into clinical routine diagnosis, assay sensitivity increased to 0.01 mU/L, allowing a clear-cut discrimination of the normal thyroid state from both hypothyroidism and hyperthyroidism [3]. In the present paper, we address the current use of TSH as the dominant parameter in thyroid function testing, explain some major limitations of this approach, and attempt to suggest areas of possible improvement. The fact that TSH is a measure of regulatory control with widely varying set-points among individuals rather than an outcome variable with a tight uniform range has various consequences for the statistical interpretation of this parameter, which …