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An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone

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An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone International Journal of Molecular Sciences Review An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Thyroid-Stimulating Hormone Kenji Ohba 1,2 1 Medical Education Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan; [email protected]; Tel./Fax: +81-53-435-2843 2 Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan Abstract: Inappropriate secretion of thyroid-stimulating hormone (IST), also known as central hy- perthyroidism, is a clinical condition characterized by elevated free thyroxine and triiodothyronine concentrations concurrent with detectable thyroid-stimulating hormone (TSH) concentrations. Simi- larly, the term syndrome of IST (SITSH) is widely used in Japan to refer to a closely related condition; however, unlike that for IST, an elevated serum free triiodothyronine concentration is not a requisite criterion for SITSH diagnosis. IST or SITSH is an important indicator of resistance to thyroid hormone β (RTHβ) caused by germline mutations in genes encoding thyroid hormone receptor β (TRβ) and TSH-secreting pituitary adenoma. Recent evidence has accumulated for several conditions associated with IST, including RTH without mutations in the TRβ gene (non-TR-RTH), the phenomenon of hysteresis involving the hypothalamus-pituitary-thyroid axis (HPT-axis), methodological interfer- ence, and Cushing’s syndrome after surgical resection. However, little information is available on the systematic pathophysiological aspects of IST in previous review articles. This report presents an overview of the recent advances in our understanding of the etiological aspects of IST that are relevant for diagnosis and treatment. Moreover, the report focuses on the potential mechanism of IST caused by hysteresis in the HPT-axis (lagging TSH recovery) in terms of epigenetic regulation. Citation: Ohba, K. An Update on the Pathophysiology and Diagnosis of Inappropriate Secretion of Keywords: thyroid function; inappropriate secretion of thyroid-stimulating hormone (IST); Thyroid-Stimulating Hormone. Int. J. syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH); genuine IST Mol. Sci. 2021, 22, 6611. https:// doi.org/10.3390/ijms22126611 Academic Editor: Noriyuki Koibuchi 1. Introduction Circulating concentrations of thyroid-stimulating hormone (TSH) and other thyroid Received: 7 June 2021 hormones are tightly regulated in healthy individuals [1]. The liganded thyroid hormone Accepted: 17 June 2021 receptor (TR) negatively regulates the synthesis and secretion of TSH in pituitary thy- Published: 21 June 2021 rotrophs, resulting in drastic decreases in serum TSH concentrations [2]. For example, the most common forms of hyperthyroidism, including Graves’ disease and toxic multinodular Publisher’s Note: MDPI stays neutral goiter, demonstrate elevated thyroid hormone levels with suppressed TSH concentrations. with regard to jurisdictional claims in Inappropriate secretion of TSH (IST) is characterized by the laboratory findings of published maps and institutional affil- elevated free thyroxine (T ) and triiodothyronine (T ) concentrations in the presence of iations. 4 3 detectable TSH concentrations [3,4], contrary to what happens in the most common forms of hyperthyroidism (Figure1A). This abnormal pattern in the thyroid function test is an im- portant hallmark of genetic and acquired disorders of the hypothalamus-pituitary-thyroid axis (HPT-axis), including resistance to thyroid hormone β (RTHβ) caused by germline Copyright: © 2021 by the author. mutations in genes encoding the β isoform of the TR (TRβ) and TSH-secreting pituitary Licensee MDPI, Basel, Switzerland. adenoma (TSHoma). Although previous review articles have sufficiently investigated This article is an open access article several conditions associated with IST, little information is available on systematic patho- distributed under the terms and physiological aspects of IST in previous review articles. In addition, a recent study has conditions of the Creative Commons revealed that diagnostic delay and inappropriate treatments (e.g., pituitary surgeries in Attribution (CC BY) license (https:// β creativecommons.org/licenses/by/ patients with RTH or thyroid ablation in patients with TSHoma) are still provided in 4.0/). several cases with thyroid hormone profiles suggestive of IST [5]. Int. J. Mol. Sci. 2021, 22, 6611. https://doi.org/10.3390/ijms22126611 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 11 addition, a recent study has revealed that diagnostic delay and inappropriate treatments (e.g., pituitary surgeries in patients with RTHβ or thyroid ablation in patients with Int. J. Mol. Sci. 2021, 22, 6611 2 of 11 TSHoma) are still provided in several cases with thyroid hormone profiles suggestive of IST [5]. ABSubclinical hypothyroidism TSH IST or range Within reference FT4 and FT3 FT4 Low High Within Low reference High Serum TSH concentration range IST SITSH Serum FT4 and FT3 concentrations Figure 1.1. TheThe differentdifferent hormonehormone profilesprofiles of of inappropriate inappropriate secretion secretion of of thyroid-stimulating thyroid-stimulating hormone hormone (IST) (IST) and and syndrome syndrome of ISTof IST (SITSH). (SITSH). (A) ( AA) schematic A schematic explanation explanation of the of difference the difference between between IST and IST SITSH. and SITSH. Note thatNote an that elevated an elevated free triiodothyro- free triio- ninedothyronine (FT3) concentration (FT3) concentration is a requisite is a requisite diagnostic diagnostic criterion criterion for IST. (forB) AIST. schematic (B) A schematic explanation explanation of the difference of the difference between ISTbetween and subclinicalIST and subclinical hypothyroidism. hypothyroidi Thesm. shaded The shaded region andregion striped and striped region representregion represent the areas the of areas IST andof IST subclinical and sub- clinical hypothyroidism, respectively. FT4, free thyroxine. hypothyroidism, respectively. FT4, free thyroxine. In this article, the author has performed a review of literature and has presented a balanced overview ofof thethe recentrecent advances advances in in our our understanding understanding of of the the clinical, clinical, biochemical, biochem- ical,and etiologicaland etiological aspects aspects of IST ofrelevant IST relevant for its for diagnosis. its diagnosis. 2. Definition Definition of IST The term “IST” waswas proposedproposed byby GershengornGershengorn and and Weintraub Weintraub in in 1975 1975 [6 [6].]. In In a a subse- sub- sequentquent report, report, IST IST was was described described as as a conditiona condition characterized characterized by by elevated elevated serum serum levels levels of ofimmunoreactive immunoreactive TSH TSH in thein the presence presence of elevatedof elevated free free thyroid thyroid hormone hormone concentrations concentrations [3]. [3].However, However, it has it has been been suggested suggested that that TSH TS secretionH secretion is compensatory is compensatory and and appropriate appropriate in inRTH RTHβ,β because, because the the response response to to thyroid thyroid hormones hormones in peripheralin peripheral tissues tissues is reducedis reduced due due to toimpairment impairment of theof the TR TR [7]. [7]. Beck-Peccoz Beck-Peccoz et al.et al. also also suggested suggested that that the the definition definition of “IST” of “IST” ap- appearspears inadequate, inadequate, as itas does it does not reflect not reflect the pathophysiological the pathophysiological events underlying events underlying TSHoma TSHomaand RTH βand[4]. RTH Therefore,β [4]. theTherefore, authors proposedthe authors the proposed term “central the hyperthyroidism”term “central hyperthy- instead roidism”of IST, because instead TSH of IST, itself because is responsible TSH itself for theis responsible hyperstimulation for the ofhyperstimulation the thyroid gland ofand the thyroidthe consequent gland and thyrotoxicosis. the consequent thyrotoxicosis. The term “syndrome of inappropriateinappropriate secretionsecretion ofof thyroid-stimulatingthyroid-stimulating hormonehormone (SITSH)” has has been been widely widely used used in in journal journal ar articlesticles and and textbooks textbooks written written by byJapanese Japanese re- searchersresearchers since since the the late late 1980s. 1980s. Based Based on on th thee 2016 2016 Japan Japan Thyroid Thyroid Association Association (JTA) (JTA) guide- guide- β lines for the diagnosis of RTHβ, SITSH is defineddefined as being characterized by elevatedelevated freefree T and normal-to-elevated TSH concentrations [8] (Figure1A). An elevated serum free T4 and normal-to-elevated TSH concentrations [8] (Figure 1A). An elevated serum free T3 Tconcentration3 concentration is not is not a requisite a requisite criterion criterion for for SITSH SITSH diagnosis. diagnosis. In In this this study, study, the author conducted a MEDLINE search using the keyword “SITSH” to retrieve relevant articles pub- conducted a MEDLINE search using the keyword “SITSH” to retrieve relevant articles lished between 1975 and 2020. The literature search yielded 30 articles, of which 28 were published between 1975 and 2020. The literature search yielded 30 articles, of which 28 published in Japanese institutions. were published in Japanese institutions. Physicians must keep in mind
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