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.
Journal Article Prognostic value of TSAb- and TBII-activity in the follow-up of patients with Graves' disease on methimazole treatment Get access R Hörmann, R Hörmann Medizinische Klinik II, Klinikum Großhadern, Universität München Search for other works by this author on: Oxford Academic Google Scholar B Saller, B Saller Medizinische Klinik II, Klinikum Großhadern, Universität München Search for other works by this author on: Oxford Academic Google Scholar R Müller, R Müller Medizinische Klinik II, Klinikum Großhadern, Universität München Search for other works by this author on: Oxford Academic Google Scholar K Mann K Mann Medizinische Klinik II, Klinikum Großhadern, Universität München Search for other works by this author on: Oxford Academic Google Scholar Acta Endocrinologica (Norway), Volume 110, Issue 1_Supplement_a, Apr 1979, Pages S68–S69, https://doi.org/10.1530/acta.0.109S068 Published: 01 April 1985
Current therapy of Graves' disease is symptomatically effective in eliminating hyperthyroidism but is not directed towards the immunological cause of the disease. As a result, the majority of patients experience relapse of hyperthyroidism after antithyroid drugs have been discontinued and need to undergo radioiodine treatment or surgery. Improvement of efficacy of antithyroid drug therapy in inducing longlasting remission of Graves' disease has therefore been an elusive goal. A number of recent experimental and clinical trials have addressed the issue of improving and optimizing modalities of antithyroid therapy. In-vitro studies demonstrating direct immunosuppressive effects of thionamide drugs and encouraging results from a Japanese clinical trial suggested that maximum thyroid blockade and supplementation with levothyroxine might be effective in preventing relapse of disease. The superior efficacy of this approach could not be confirmed by others studies. On the other hand, these studies so far lack statistical power to prove a lack of effect of this approach. The issue of levothyroxine supplementation during antithyroid drug treatment should be separated from another issue of levothyroxine prophylaxis following successful treatment outcome. The latter question is currently addressed by a prospective randomized multicenter study.
The close relationship between thyroid microsomal antigen and thyroid peroxidase (TPO) is now well established. The present study evaluates the significance of autoantibodies against TPO (anti-TPO-Abs) in the various forms and stages of autoimmune thyroid disease with respect to a possible heterogeneous nature and particularly to their influence on TPO activity. When measured by a RIA using purified human TPO, anti-TPO-Abs were highly correlated with microsomal antibodies determined by enyzme-linked immunosorbant assay (r = 0.96; P < 0.0001) and with the results of a TPO immunoprecipitation assay using crude microsomal preparations (r = 0.76; P < 0.001). Relating the results of these assays to the reactivities of patients' sera with thyroid microsomes in immunoblot under nonreducing and reducing conditions, discordant results could be observed in a few cases. Further analysis of these data indicate a heterogeneous nature of anti-TPO-Abs, which react with at least two antigenic domains of the TPO molecule. The comparative analysis of patients with hyperthyroid Graves' disease, patients with Graves' disease in clinical remission, and patients with hypothyroid Hashimoto's thyroiditis revealed no significant differences in the antibody spectrum. When evaluating the direct influence of anti-TPO-Abs on the activity of TPO under a rigorous methodological approach, we found no significant inhibition of the enzymatic activity by any of the sera investigated from patients with autoimmune thyroid disease compared to that in sera from normal controls. In conclusion, the data indicate a heterogeneous nature of anti-TPO-Abs. The spectrum of antigenic epitopes recognized by anti-TPO-Abs seems not to be significantly different in the various forms and stages of autoimmune thyroid disease. The lack of an inhibitory effect of autoantibodies on TPO activity argues against direct binding of autoantibodies to the enzymatic sites of TPO and indicates that they are not important factors in producing thyroid dysfunction in autoimmune thyroid disease.
