Clinical Relevance of Environmental Factors in the Pathogenesis of Autoimmune Thyroid Disease.

Genetic factors contribute for about 70% to 80% and environmental factors for about 20% to 30% to the pathogenesis of autoimmune thyroid disease (AITD). Relatives of AITD patients carry a risk to contract AITD themselves. The 5-year risk can be quantified by the so-called Thyroid Events Amsterdam-score, based on serum thyroid-stimulating hormone, thyroid peroxidase (TPO)-antibodies and family history. Subjects at risk may ask what they can do to prevent development of AITD. This review summarizes what is known about modulation of exposure to environmental factors in terms of AITD prevention. To stop smoking decreases the risk on Graves disease but increases the risk on Hashimoto disease. Moderate alcohol intake provides some protection against both Graves and Hashimoto disease. Low selenium intake is associated with a higher prevalence of thyroid autoimmunity, but evidence that selenium supplementation may lower TPO antibodies and prevent subclinical hypothyroidism remains inconclusive. Low serum vitamin D levels are associated with a higher prevalence of TPO antibodies, but intervention studies with extra vitamin D have not been done yet. Stress may provoke Graves hyperthyroidism but not Hashimoto thyroiditis. Estrogen use have been linked to a lower prevalence of Graves disease. The postpartum period is associated with an increased risk of AITD. Taking together, preventive interventions to diminish the risk of AITD are few, not always feasible, and probably of limited efficacy.

The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy.

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.

Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies.

CONTEXT: Euthyroid thyroid peroxidase (TPO-Ab)-positive subjects are at risk for progression to subclinical and overt autoimmune hypothyroidism. Previous studies have shown a decrease in TPO-Ab and improvement of quality-of-life (QoL) in L-T4-treated hypothyroid patients upon selenium supplementation. OBJECTIVES: To evaluate in euthyroid TPO-Ab-positive women without thyroid medication whether selenite decreases TPO-Ab and improves QoL. DESIGN: Randomized, placebo-controlled, double-blind study. PATIENTS AND METHODS: Euthyroid (TSH 0·5-5·0 mU/l, FT4 10-23 pm) women with TPO-Ab ≥ 100 kU/l were randomized to receive 200 mcg sodium selenite daily (n = 30) or placebo (n = 31) for 6 months. TSH, FT4, TPO-Ab, selenium (Se), selenoprotein P (SePP) and QoL were measured at baseline, 3, 6 and 9 months. RESULTS: There were no differences in baseline characteristics between the Se group and the placebo group. During selenite supplementation, serum Se and SePP did not change in the placebo group, but increased in the Se group. TPO-Ab and TSH did not change significantly in any group. TPO-Ab in the Se group were 895 (130-6800) at baseline, 1360 (60-7050) kU/l at 6 months, in the placebo group 1090 (120-9200) and 1130 (80-9900) kU/l, respectively (median values with range). TSH in the Se group was 2·1 (0·5-4·3) at baseline, 1·7 (0·0-5·3) mU/l at 6 months, in the placebo group 2·4 (0·7-4·4) and 2·5 (0·2-4·3) mU/l, respectively. QoL was not different between the groups. CONCLUSION: Six months selenite supplementation increased markers of selenium status but had no effect on serum TPO-Ab, TSH or quality-of-life in euthyroid TPO-Ab-positive women.

Action of specific thyroid hormone receptor α(1) and ß(1) antagonists in the central and peripheral regulation of thyroid hormone metabolism in the rat.

BACKGROUND: The iodine-containing drug amiodarone (Amio) and its noniodine containing analogue dronedarone (Dron) are potent antiarrhythmic drugs. Previous in vivo and in vitro studies have shown that the major metabolite of Amio, desethylamiodarone, acts as a thyroid hormone receptor (TR) α(1) and ß(1) antagonist, whereas the major metabolite of Dron debutyldronedarone acts as a selective TRα(1) antagonist. In the present study, Amio and Dron were used as tools to discriminate between TRα(1) or TRß(1) regulated genes in central and peripheral thyroid hormone metabolism. METHODS: Three groups of male rats received either Amio, Dron, or vehicle by daily intragastric administration for 2 weeks. We assessed the effects of treatment on triiodothyronine (T(3)) and thyroxine (T(4)) plasma and tissue concentrations, deiodinase type 1, 2, and 3 mRNA expressions and activities, and thyroid hormone transporters monocarboxylate transporter 8 (MCT8), monocarboxylate transporter 10 (MCT10), and organic anion transporter 1C1 (OATP1C1). RESULTS: Amio treatment decreased serum T(3), while serum T(4) and thyrotropin (TSH) increased compared to Dron-treated and control rats. At the central level of the hypothalamus-pituitary-thyroid axis, Amio treatment decreased hypothalamic thyrotropin releasing hormone (TRH) expression, while increasing pituitary TSHß and MCT10 mRNA expression. Amio decreased the pituitary D2 activity. By contrast, Dron treatment resulted in decreased hypothalamic TRH mRNA expression only. Upon Amio treatment, liver T(3) concentration decreased substantially compared to Dron and control rats (50%, p<0.01), but liver T(4) concentration was unaffected. In addition, liver D1, mRNA, and activity decreased, while the D3 activity and mRNA increased. Liver MCT8, MCT10, and OATP1C1 mRNA expression were similar between groups. CONCLUSION: Our results suggest an important role for TRα1 in the regulation of hypothalamic TRH mRNA expression, whereas TRß plays a dominant role in pituitary and liver thyroid hormone metabolism.

Hypothalamic thyroid hormone feedback in health and disease.

The role of the human hypothalamus in the neuroendocrine response to illness has only recently begun to be explored. Extensive changes in the hypothalamus-pituitary-thyroid (HPT) axis occur within the framework of critical illness. The best-documented change in the HPT axis is a decrease in serum concentrations of the biologically active thyroid hormone triiodothyronine (T3). From studies in post-mortem human hypothalamus it appeared that low serum T3 and thyrotropin (TSH) during illness (nonthyroidal illness, NTI) are paralleled by decreased thyrotropin-releasing hormone (TRH)mRNA expression in the hypothalamic paraventricular nucleus (PVN), pointing to a major alteration in HPT axis setpoint regulation. A strong decrease in TRHmRNA expression is also present in the PVN of patients with major depression as well as in glucocorticoid-treated patients. By inference, hypercortisolism in hospitalized patients with severe depression or in critical illness may induce down-regulation of the HPT axis at the level of the hypothalamus. In order to start defining the determinants and mechanisms of these setpoint changes in various clinical conditions, it is important to note that an increasing number of hypothalamic proteins appears to be involved in central thyroid hormone metabolism. In recent studies, we have investigated the distribution and expression of thyroid hormone receptor (TR) isoforms, type 2 and type 3 deiodinase (D2 and D3), and the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in the human hypothalamus by a combination of immunocytochemistry, mRNA in situ hybridization and enzyme activity assays. Both D2 and D3 enzyme activities are detectable in the mediobasal hypothalamus. D2 immunoreactivity is prominent in glial cells of the infundibular nucleus/median eminence region and in tanycytes lining the third ventricle. Combined D2, D3, MCT8 or TR immunocytochemistry and TRHmRNA in situ hybridization indicates that D3, MCT8 and TRs are all expressed by TRH neurons in the PVN, whereas D2 is not. Taken together, these results suggest that the prohormone thyroxine (T4) is taken up in glial cells that convert T4 into the biologically active T3 via the enzyme D2; T3 is subsequently transported to TRH producing neurons in the PVN where it may bind to TRs and/or may be degraded into inactive iodothyronines by D3. This model for thyroid hormone action in the human hypothalamus awaits confirmation in future experimental studies.

Neuroanatomical pathways for thyroid hormone feedback in the human hypothalamus.

CONTEXT: Recent findings point to an increasing number of hypothalamic proteins involved in the central regulation of thyroid hormone feedback. The functional neuroanatomy of these proteins in the human hypothalamus is largely unknown at present. OBJECTIVE: The aim of this study was to report the distribution of type II and type III deiodinase (D2 and D3) as well as the recently identified T(3) transporter, monocarboxylate transporter 8 (MCT8), in the human hypothalamus. DESIGN: The study included enzyme activity assays, immunocytochemical studies, and mRNA in situ hybridizations in postmortem human hypothalamus (n = 9). RESULTS: D2 immunoreactivity is prominent in glial cells of the infundibular nucleus/median eminence, blood vessels, and cells lining the third ventricle. By contrast, both D3 and MCT8 are expressed by neurons of the paraventricular (PVN), supraoptic, and infundibular nucleus (IFN). In support of these immunocytochemical data, D2 and D3 enzyme activities are detectable in the mediobasal human hypothalamus. Combined D2, D3, MCT8, and thyroid hormone receptor immunohistochemistry and TRH mRNA in situ hybridization clearly showed that D3, MCT8, and thyroid hormone receptor isoforms are all expressed in TRH neurons of the PVN, whereas D2 is not. CONCLUSIONS AND IMPLICATIONS: Based on these findings, we propose three possible routes for thyroid hormone feedback on TRH neurons in the human PVN: 1) local thyroid hormone uptake from the vascular compartment within the PVN, 2) thyroid hormone uptake from the cerebrospinal fluid in the third ventricle followed by transport to TRH neurons in the PVN or IFN neurons projecting to TRH neurons in the PVN, and 3) thyroid hormone sensing in the IFN of the mediobasal hypothalamus by neurons projecting to TRH neurons in the PVN.

Thyroid hormone receptor expression in the human hypothalamus and anterior pituitary.

In the present study, we describe for the first time the distribution of thyroid hormone receptor (TR) isoforms in the human postmortem hypothalamus and anterior pituitary using immunocytochemistry. We used a set of polyclonal antisera raised against the specific isoforms of the human TR. The distribution of TR alpha 1, alpha 2, beta 1, and beta 2 was studied in consecutive sections of six hypothalami and pituitaries. Staining intensity showed strong interindividual variation but was consistently present in the infundibular nucleus, paraventricular nucleus, and supraoptic nucleus. In addition, strong TR immunoreactivity was observed in the anterior pituitary. Neuropeptide Y and proopiomelanocortin mRNA-positive cells in the infundibular nucleus, which were studied in three other hypothalami, appeared not to express TRs, and thus, the neurons expressing TRs in the human mediobasal hypothalamus remain to be characterized.