Part 2 book “Thyroid diseases - Pathogenesis, diagnosis, and treatment” has contents: Central hypothyroidism, diagnosis and treatment of hypothyroidism, toxic adenoma and multinodular toxic goiter, medullary carcinoma, anaplastic and other forms of thyroid carcinoma, non- thyroidal illness,… and other contents.
Central Hypothyroidism 12 Andrea Lania, Claudia Giavoli, and Paolo Beck-Peccoz Contents Epidemiology Etiopathogenesis Congenital CH Acquired Clinical and Biochemical Presentation Treatment and Follow-Up Summary Cross-References References 374 374 376 378 380 382 384 385 385 Abstract Central hypothyroidism (CH) is a clinical condition characterized by a defect in thyroid hormone secretion due to an insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland CH is a rare and heterogeneous disorder that is caused by abnormalities of either the pituitary gland or the hypothalamus, and it may be congenital or acquired The clinical manifestations are usually milder than those observed in primary hypothyroidism, and the CH diagnosis is A Lania (*) Department of Medical Sciences, Humanitas University and Endocrinology Unit, Humanitas Research Hospital, Rozzano, Italy e-mail: andrea.lania@humanitas.it C Giavoli Endocrinology and Metabolic Diseases Unit, Fondazione IRCCS Cà Granda-Ospedale Maggiore, Milano, Italy e-mail: giavoli@yahoo.it P Beck-Peccoz University of Milan, Milano, Italy e-mail: paolo.beckpeccoz@unimi.it # Springer International Publishing AG, part of Springer Nature 2018 P Vitti, L Hegedüs (eds.), Thyroid Diseases, Endocrinology, https://doi.org/10.1007/978-3-319-45013-1_13 373 374 A Lania et al based on low circulating levels of free thyroid hormone and low/normal TSH CH treatment is based on L-thyroxine (L-T4) supplementation, the adequacy of which is evaluated by measuring circulating free thyroxine (FT4) This chapter analyzes our current understanding of the causes of CH and highlights possible pitfalls in its diagnosis and treatment Keywords Central hypothyroidism · L-thyroxine · Hypopituitarism Epidemiology Central hypothyroidism (CH) is a clinical condition characterized by a defect in thyroid hormone secretion due to an insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland CH is a rare and heterogeneous disease caused by abnormalities of either the pituitary gland (i.e., secondary hypothyroidism) or the hypothalamus (i.e., tertiary hypothyroidism) The prevalence of CH ranges from 1:20,000 to 1:80,000 individuals in the general population (Price and Weetman 2001) and represents an uncommon cause of hypothyroidism (one of 1,000 hypothyroid patients) As far as congenital CH is concerned, its prevalence depends on the screening protocols adopted In fact, when TSH-only-based protocols are used, CH is often unrecognized since it is usually associated with inappropriately normal/low TSH in the presence of low circulating FT4 levels When screening programs for neonatal CH include both TSH and FT4 measurements, its prevalence increases to 1:160,000 (Asakura et al 2002; Nebesio et al 2010) Interestingly, CH prevalence further increases to in 16,000 newborns if the screening algorithm is based on the combined measurement of TSH, T4, and thyroxine-binding globulin, which could be effective in diagnosing the milder forms of the disease (Kempers et al 2006) While primary hypothyroidism is mainly diagnosed in females (incidence 3.5:1000 in females vs 0.6:1000 in males), CH affects patients of all ages and equally in both sexes Etiopathogenesis CH may be congenital or acquired (Table 1) and is caused by anatomical and/or functional abnormalities affecting either the pituitary (secondary hypothyroidism) or the hypothalamus (tertiary hypothyroidism) It is worth noting that in many instances, both the pituitary and the hypothalamus may be affected simultaneously A quantitative defect in the amount of functional pituitary thyrotroph cells (i.e., thyrotropin reserve) is probably the pathogenic mechanism underlying most acquired CH cases This quantitative defect in thyrotrophs is associated with a qualitative defect in the secreted TSH isoforms, which display an impaired 12 Central Hypothyroidism 375 Table Causes of central hypothyroidism Acquired Invasive Causes Pituitary macroadenomas, craniopharyngiomas, meningiomas, gliomas, metastases, carotid aneurysms Iatrogenic Cranial surgery or irradiation, drugs (e.g., bexarotene) Injury Head trauma, traumatic delivery Immunologic lesions Lymphocytic hypophysitis Infarction Postpartum necrosis (Sheehan), pituitary apoplexy Infiltrative lesions Sarcoidosis, hemochromatosis, histiocytosis X Infective lesions Tuberculosis, syphilis, mycoses Congenital Isolated TSH beta, TRHR, IGSF1 Combined HESX1, LHX3, LHX4, SOX3, OTX2, PROP1, POU1F1 TRHR, TRH receptor; IGSF1, immunoglobulin superfamily member 1; HESX1, homeobox gene expressed in ES cells; LIM domain transcription factors and 4, LHX3 and LHX4; SOX3, SRY-related HMG-box gene 3; OTX2, orthodenticle homeobox 2; PROP1, prophet of PIT1; POU1F1, POU domain class transcription factor biological activity and ability to bind thyroid TSH receptors despite a preserved immunoreactivity (Persani et al 2000) In this setting, circulating levels of immunoreactive TSH may be normal or even slightly increased (Beck-Peccoz et al 1985) Importantly, the secretion of bioinactive TSH is often related to CH forms associated with an impaired hypothalamic function (i.e., tertiary hypothyroidism) In this respect, studies have shown that the impaired biological activity of TSH observed in these patients is caused by changes in TSH carbohydrate structure leading to an impaired glycosylation (Papandreou et al 1993; Persani et al 1998) In congenital CH, defects in TSH secretion may be quantitative and/or qualitative according to the cause of the disease In this respect, in patients with loss of function TSH beta gene mutations, CH is caused by “abnormal” TSH molecules lacking part of the C-terminal amino acid sequence Some of these TSH beta mutants are unable to heterodimerize with the alpha subunit and are therefore inactive (Beck-Peccoz et al 2006) Other mutations may form an incomplete heterodimer with preserved immunoreactivity in some of the methods for TSH measurement but completely devoid of bioactivity (Bonomi et al 2001) 376 A Lania et al Congenital CH Congenital CH may be classified as isolated or combined (Table 2) Isolated congenital CH is caused by mutations affecting genes coding for TSH beta, TRH receptor (TRHR), or immunoglobulin superfamily member (IGSF1) (Shoenmakers et al 2015) In the majority of patients, congenital CH is associated with different pituitary hormone deficiencies (combined CH), and some additional syndromic features may be present depending on the genes involved (Schoenmakers et al 2015) Isolated CH TSH beta gene mutations cause severe CH of neonatal onset leading to impaired neurodevelopment Neurological alterations associated with TSH beta mutations are related to treatment delay because affected subjects are not recognized by TSH-based CH screening programs and remain undiagnosed until the neurological consequences of the severe hypothyroidism are clinically manifest Biallelic TRHR gene mutations represent an uncommon cause of isolated congenital CH These Table Congenital forms of CH: clinical presentation Gene TSH beta TRHR IGSF1 POUF1 PROP1 HESX1 LHX3 LHX4 SOX3 OTX2 Pituitary function CH CH, HYP CH, GHD (transient), HYP CH, HYP, GHD CH, GHD, CHY, CHA (late) CH, GHD, CHY, CHA (late) CH, GHD, CHY, HYP CH, GHD, CHY (variable), CHA CH, GHD, CHY, CHA CH, GHD, CHY, CHA Other clinical features Neuroradiological findings Enlarged/normal pituitary Macroorchidism Septo-optic dysplasia Limited neck rotation, short cervical spine, sensorineural deafness Cerebellar abnormalities Mental retardation Anopthalmy Retinal abnormalities Variable pituitary hypoplasia Enlarged/normal/hypoplastic pituitary Pituitary hypoplasia Enlarged/normal/hypoplastic pituitary Pituitary hypoplasia Pituitary hypoplasia Variable pituitary hypoplasia GHD, growth hormone deficiency; CH, central hypothyroidism; CHY, central hypogonadism; HYP, hypoprolactinemia; CHA, central hypoadrenalism; TRHR, TRH receptor; IGSF1, immunoglobulin superfamily member 1; PROP1, prophet of PIT1; POU1F1, POU domain class transcription factor 1; HESX1, homeobox gene expressed in ES cells; LIM domain transcription factors and 4, LHX3 and LHX4; SOX3, SRY-related HMG-box gene 3; OTX2, orthodenticle homeobox 12 Central Hypothyroidism 377 mutations have so far been described in just three cases from two unrelated kindred Affected males present subnormal T4 concentrations, growth retardation, and delayed bone age Conversely, no neurological deficits (i.e., mental retardation) have been described in these patients IGSF1 deficiency has recently been identified as an X-linked cause of CH and macroorchidism (Sun et al 2012) A multicentric study has recently analyzed all clinical and biochemical characteristics associated with IGSF1 deficiency in a series of 42 patients (Joustra et al 2013) In particular, the authors observed that in male patients CH is associated with hyperprolactinemia (67% of cases) and transient GH deficiency (13% of cases) Though puberty is delayed (including the growth spurt and pubic hair development), testicular growth starts at a normal age, and macroorchidism is described in all evaluable adults Notably, body mass index, percent fat, and waist circumference are increased, with presence of the metabolic syndrome in the majority of patients above 55 years of age Heterozygous female carriers have CH in 33% of cases, and, as observed in affected males, body mass index, percent fat, and waist circumference are relatively high Combined CH LHX3 and LHX4 are LIM domain transcription factors involved in the early steps of pituitary development Patients bearing LHX3 mutations present GH, TSH, and LH/FSH deficiencies, while central hypoadrenalism is inconsistently reported (Schoenmakers et al 2015) Brain imaging studies reveal pituitary aplasia or hypoplasia in 60% of cases and hyperplasia in 30% of cases (Schoenmakers et al 2015) Patients with LHX3 mutations may present extrapituitary disorders such as vertebral abnormalities, variable hearing alterations, and limited head and neck rotation (Netchine et al 2000) LHX4 mutations lead to GH and variable LH/FSH, TSH, and ACTH deficiencies, anterior pituitary hypoplasia, hypoplastic sella turcica, cerebellar alterations, or Chiari malformation (Rochette et al 2015) Septo-optic dysplasia (SOD) is characterized by the combination of optic nerve hypoplasia and/or midline forebrain defects (i.e., agenesis of the corpus callosum, absent septum pellucidum) and/or hypopituitarism associated with pituitary hypoplasia (McCabe et al 2011) Mutations affecting homeobox gene expressed in ES cells (HESX1), SRY-related HMG-box gene (SOX3), and orthodenticle homeobox (OTX2) genes have been found in patients with CH and SOD HESX1 expression occurs early in the pituitary placode, and its reduction is necessary for prophet of PIT1 (PROP1) and POU domain class transcription factor (POU1F1) expression, leading to differentiation of GH-, TSH-, and PRL-secreting cells Patients with homozygous mutations are usually characterized by a more severe phenotype While GH deficiency is diagnosed in all patients, other pituitary deficiencies, including CH, are found in 50% of cases Optic nerve anomalies are observed in 30% of cases, and MRI imaging reveals pituitary hypoplasia in 80% of cases, ectopic posterior pituitary in 50–60%, and corpus callosum agenesis or hypoplasia in 25% of cases OTX2 is a paired homeodomain transcription factor involved in the early steps of brain development OTX2 mutations are responsible for 2–3% of anophthalmia/ microphthalmia syndromes in humans Pituitary deficiencies range from isolated GH deficiency to panhypopituitarism Brain MRI may reveal normal or hypoplastic 378 A Lania et al pituitary Moreover, ectopic posterior pituitary or Chiari syndrome may be identified in these patients Mutations affecting the SOX3 gene lead to X-linked hypopituitarism, ranging from isolated growth hormone deficiency to combined pituitary hormone deficiency, including evolving TSH deficiency (Stagi et al 2014) PROP1 is a pituitary-specific paired-like homeodomain transcription factor Its expression is required for the development of GH-, PRL-, and TSH-secreting pituitary cells (i.e., POU1F1 lineage) PROP1 mutations are the most common cause of combined pituitary hormone deficiency and are associated with GH, TSH, LH/FSH, ACTH, and PRL deficiencies that may be diagnosed from childhood to adulthood (Fluck et al 1998) Neuroradiological imaging studies can show transient pituitary hyperplasia or a normal or hypoplastic pituitary Pituitary hyperplasia sometimes precedes spontaneous hypoplasia POU1F1 is expressed relatively late during pituitary development and its expression persists in adulthood POU1F1 is required for the production of GH, PRL, and TSH beta as well as for the expression of GHRH receptor Patients with autosomal recessive and dominant POU1F1 mutations are characterized by GH and PRL deficiency, which is normally present from early life In contrast, TSH deficiency may be highly variable and hypothyroidism may occur later in childhood In these patients, MRI shows a normal or a hypoplastic anterior pituitary Acquired Neoplasias, affecting the hypothalamus-pituitary region as well as therapeutic interventions on sellar and extrasellar tumor masses (i.e., surgery and radiotherapy), represent the most frequent causes of acquired CH In particular, pituitary macroadenomas may induce hypopituitarism by affecting either pituitary cells or the pituitary stalk In this respect, nonfunctioning pituitary adenomas are the tumors most frequently involved At presentation, isolated or multiple pituitary deficits are diagnosed in 62% of patients with pituitary nonfunctioning macroadenomas, with CH found in 27% of them (Ferrante et al 2008; Dekkers et al 2008) The risk and extent of postsurgical hypopituitarism depend on tumor size, tumor extension, and the experience of the surgeon In particular, new pituitary hormone deficiency is described in 10% of patients who have undergone pituitary surgery in referral centers, with CH occurring in less than 3% of such cases (Losa et al 2013) Craniopharyngiomas are typically slowly growing extrasellar tumors, and visual field defects and hypopituitarism are the most common presenting clinical manifestations In children, GH deficiency is the most common pituitary deficit diagnosed at presentation (up to 100% of patients), followed by TSH deficiency (up to 25% of patients) In adults, CH has been described in 40% of cases, growth hormone deficiency in 80–90% of cases, gonadotropin deficiency in 70% of patients, and ACTH in 40% of patients (Karavitaki et al 2005, 2006; Muller 2014) Surgical intervention is associated with hypopituitarism in the majority of patients with craniopharyngiomas, with CH reported in 40 to 95% of cases (Karavitaki et al 2006; Muller 2014) 12 Central Hypothyroidism 379 Importantly, hypopituitarism may occur in patients who undergo neurosurgical intracranial procedures for conditions other than pituitary tumors In this setting, the main pituitary hormone deficiencies are related to ACTH, GH, and LH/FSH insufficiency and only rarely to TSH insufficiency (Fleck et al 2013) Direct and indirect irradiation of the hypothalamic-pituitary axis may cause hypopituitarism The risk of developing CH is related to both the effective dose given to the area and the total radiation dose delivered (Kanumakala et al 2003; Schmiegelow et al 2003) Radiation-induced CH occurs in patients who undergo radiotherapy, not only for pituitary tumors and craniopharyngiomas but also in 10–50% of patients irradiated for nasopharyngeal or paranasal sinus tumors (Samaan et al 1987; Ratnasingam et al 2015) and in 12–65% of patients irradiated for any site brain tumors (Constine et al 1993; Kyriakakis et al 2016) Unfortunately, data on the long-term effects on hypothalamic-pituitary function of proton beam therapy – whether by Leksell Gamma Knife or stereotactic linear accelerator – are still scarce and inconclusive However, recent findings suggest that hypopituitarism (including CH) occurs even after these new irradiation methods (Xu et al 2013) Analyses of the effects of Leksell Gamma Knife on pituitary function in a series of patients affected with Cushing’s disease have demonstrated that new pituitary deficiency occurs in 58% of patients, with a latency of up to 160 months after radiation delivery The most commonly deficient endocrine axis was the GH (33%) followed by the gonadotroph axis (28 %) Of interest, TSH deficiency was observed in 27% of cases, while CH occurred in 5%, 10%, and 27% of patients at 3, 5, and 10 years of followup, respectively (Cohen-Inbar et al 2016) Hypopituitarism may represent the consequences of traumatic brain injury (TBI), the prevalence of anterior pituitary dysfunction ranging from 15% to 68% (Fernandez-Rodriguez et al 2015) In TBI patients CH frequency varies between series (from 5% up to 29%) (Fernandez-Rodriguez et al 2015; Krewer et al 2016), this discrepancy being possibly explained by either the timing of testing or the diagnostic procedure used to identify pituitary hormone deficiencies Cerebrovascular accidents (i.e., subarachnoid hemorrhage or infarcts) can but rarely induce hypopituitarism, with CH diagnosed in less than 2% of cases (Klose et al 2010) Granulomatous diseases (i.e., sarcoidosis, tuberculosis, and histiocytosis X), as well as all iron overload states (i.e., hemochromatosis, patients with β-thalassemia who need several blood transfusions), can induce hypopituitarism and CH by directly acting on the pituitary stalk (Gamberini et al 2008; Lewis et al 2009) Hypophysitis is a condition characterized by lymphocytic infiltration of the pituitary gland On the basis of the histopathological picture, it can be classified as lymphocytic or granulomatous (Fukuoka 2015) Hypopituitarism is the most prevalent feature of lymphocytic hypophysitis, with CH as the pituitary hormone deficiency most frequently diagnosed after central hypoadrenalism and hypogonadotropic hypogonadism In contrast, GH deficiency seems to be the least frequent (Fukuoka 2015; Honegger et al 2015) Xanthogranulomatous hypophysitis is a very rare form of pituitary hypophysitis It may either be primary (with an autoimmune etiology), secondary (as a reactive degenerative response to an epithelial lesion such as craniopharyngiomas, Rathke’s cleft cyst, germinoma, and pituitary 380 A Lania et al adenomas), or part of a multiorgan systemic disease (e.g., tuberculosis, sarcoidosis, or granulomatosis) Recently, IgG4-related hypophysitis has been frequently diagnosed as a part of IgG4-related disease This is a clinical entity characterized by IgG4 + plasma cell and lymphocyte infiltration and elevated serum IgG4 concentrations (Bando et al 2013) The growing use of anti-CTLA-4 antibody treatment (i.e., ipilimumab and tremelimumab) for several cancer types has resulted in the appearance of hypophysitis in up to 10% of treated patients (Lam et al 2015) In particular, most patients with ipilimumab-induced hypophysitis have multiple anterior pituitary hormone deficiencies CH is the most frequent (up to 90% of cases), followed by central adrenal insufficiency and hypogonadotropic hypogonadism (Faje 2016) Finally, CH has been found in adult patients characterized by the development of GH, PRL, and TSH deficiencies and the presence of detectable circulating anti-PIT-1 antibodies, the so-called anti-PIT-1 antibody syndrome (Yamamoto et al 2011) Clinical and Biochemical Presentation Clinical features of CH depend on etiology, severity of the thyroid impairment, extent and severity of associated hormone deficiencies, and age of the patient at the time of disease onset Congenital CH is clinically more severe than the acquired forms Symptoms and signs are usually the same but milder than those of primary hypothyroidism and goiter is always absent It has been proposed that residual thyrotroph function, as well as the physiological constitutive activity of the TSH receptor, may explain this discrepancy (Neumann et al 2010; Barbesino et al 2012) In the presence of combined pituitary deficiencies, other endocrine manifestations (i.e., growth failure, delayed puberty, adrenal insufficiency, and diabetes insipidus) lead the patients to seek medical attention before their hypothyroidism becomes severe In congenital CH, various syndromic and complex clinical features may be present depending on the genes involved (Table 2) (Schoenmakers et al 2015) In patients with TSH beta mutations, CH is clinically undetectable at birth, biochemically associated with elevated glycoprotein hormone alpha subunit and an impaired TSH response to TRH stimulation, and characterized by severe signs and symptoms Prolactin secretion is normal and fully responsive to TRH stimulation (Bonomi et al 2001) CH characterized by the complete absence of TSH and PRL responses to TRH is caused by inactivating TRH receptor mutations (Collu et al 1997; Bonomi et al 2009; Koulouri et al 2016) In the first reported cases, clinical manifestations were mild (growth retardation, delayed bone age) despite biochemical evidence of severe CH, with T4 levels ranging from 40% to 88% of the lower limit of normal Surprisingly, despite the late treatment, no attributable neurological deficits were found, thus suggesting sufficient childhood thyroid hormone production Importantly, T4 replacement was found effective in improving growth and quality of life in these individuals (Collu et al 1997; Bonomi et al 2009) Although the TRH receptor is expressed on lactotrophs and mediates prolactin secretion in response to exogenous TRH, a female homozygous for p.R17* TRHR underwent two pregnancies and 12 Central Hypothyroidism 381 lactated normally (Bonomi et al 2009) Immunoglobulin superfamily member (IGSF1) is an X-linked cause of CH deficiency syndrome Males with IGSF1 mutations present CH, increased body weight (in some cases metabolic syndrome has been described at adult age), macroorchidism, and sometimes hypoprolactinemia and/or transient growth hormone (GH) deficiency (Joustra et al 2013; Hulle et al 2016) A subset of female carriers (about 18%) also exhibit CH A delayed adrenarche, as a consequence of PRL deficiency, seems to be part of the clinical phenotype of patients with IGSF1 deficiency (Hughes et al 2016) Finally, mild deficits in attentional control, on formal testing, have been described in some adult male patients with IGSF1 deficiency (Joustra et al 2016) Due to the difficulties in recognizing CH clinically, the diagnosis is usually made biochemically by measuring circulating free thyroxine with direct “two-step” methods, provided that factors interfering in the assays have been ruled out (i.e., thyroid autoantibodies or abnormal binding proteins) (Gurnell et al 2011) In CH, serum TSH levels are usually low/normal or even slightly increased in patients with tertiary (hypothalamic) hypothyroidism The latter condition may be misdiagnosed as a condition of primary subclinical hypothyroidism (Koulouri et al 2013) CH is characterized by the presence of abnormalities in circadian TSH secretion leading to lack of the physiological nocturnal TSH rise, which normally demands inpatient evaluation (Darzy and Shalet 2005) A TRH stimulation test (TRH 200 mcg i.v.) has been proposed to differentiate pituitary from hypothalamic CH, the former characterized by an exaggerated/delayed and/or prolonged TSH response, which is impaired in the latter (Lania et al 2008; Fig 1) However, the practical utility of the TRH test is limited since the pituitary and the hypothalamus may be simultaneously involved in acquired CH Importantly, absent or impaired FT4 and FT3 responses, as measured at 120 and 180 after TRH injection, indirectly indicate the secretion of bioinactive TSH A 10% variation in FT4 may be considered as normal in euthyroid patients Therefore, in patients followed for pituitary diseases, a decrease in circulating FT4 25 TRH Hypothalamic CH: • delayed • exaggerated • prolonged 20 TSH mU/L Fig TRH stimulation test (TRH 200 μg i.v as a bolus) in CH diagnosis Blood for TSH measurement is withdrawn at À30, 0, 20, 60, 120, and 180 min, while FT4 and FT3 were measured at the time 0, 120, and 180 TRH test may be helpful in differentiating hypothalamic from pituitary CH, the first being characterized by an exaggerated, delayed, and/or prolonged TSH response and the second by an impaired TSH response 15 10 Pituitary CH: • impaired/absent 0 30 60 minutes 120 382 Table Clinical and biochemical features indicating possible CH A Lania et al Clinical features Presence of diseases affecting the hypothalamic-pituitary region Neuroradiological imaging demonstrating alterations in the hypothalamic-pituitary region Normal thyroid structure, at ultrasound scan Biochemical features Low FT4 and normal/low TSH levels Absence of antithyroid autoantibodies Presence of other pituitary hormone deficiencies above 20% may suggest CH, even if FT4 concentrations are still in the normal range (Alexopoulou et al 2004) Patients with nonthyroidal illnesses (NTI), a relatively common finding following any acute or chronic illness (e.g., poor nutrition/starvation, sepsis, burns, malignancy, myocardial infarction, postsurgery, chronic liver, and renal disease), display thyroid function values that considerably overlap those of CH patients (Koulouri et al 2013) It has been suggested that NTI may be due to factors such as downregulation of TRH neurons in the paraventricular nucleus, reduced TSH secretion, and modifications in thyroid hormone metabolism It is crucial to be aware of this transient phenomenon and to consider biochemical data in the context of clinical status in order to avoid inappropriate treatment In this respect, a clue for distinguishing CH from NTI is the evaluation of serum FT3, which is reduced in NTI and normal in mild to moderate forms of CH Once the biochemical diagnosis has been confirmed, a family history of CH, a suggestive clinical history (e.g., head trauma, subarachnoidal hemorrhage, previous brain irradiation, or surgery), or specific symptoms (e.g., headaches or visual field defects) should lead to a pituitary MRI and evaluation of the other hypothalamicpituitary axes In Table 3, clinical and biochemical features indicating possible CH are summarized Treatment and Follow-Up CH treatment should lead to the restoration and maintenance of euthyroidism in analogy to that intended for patients with primary hypothyroidism In this respect, L-thyroxine (L-T4) therapy is recommended since no evidence supports the superiority of combined treatment with L-T4 and triiodothyronine in either adults or children (Cassio et al 2003; Grozinsky-Glasberg et al 2006; Slawik et al 2007, and Wiersinga 2014) No consensus has been reached concerning the evaluation of the adequacy of L-T4 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687 Amiodarone, 267–268, 740 Amiodarone-induced hyperthyroidism (AIH), 76 Analytical decision model, 190 Anaplastic thyroid carcinoma (ATC), 630, 654–632 Antiangiogenesis drug therapy in thyroid cancer, 646 Antiangiogenic drug, 654 Anti-angiogenic tyrosine kinase inhibitors, 650 Anti-CTLA4 monoclonal antibodies, 748 Antiepileptic drugs (AEDs), 739 Antineoplastic agents, 744–747 Anti-PD-1 monoclonal antibodies, 749 Antithyroid drugs (ATDs), 187–188, 491–495, 528–530, 692, 695 Aromatic amino acid decarboxylase (AADC), 20 Assisted reproductive technology (ART), 688 Athyreosis, 338 Autoimmune, 453, 454, 458, 464 Autoimmune hypothyroidism, 61, 66–67 Autoimmune thyroid disease (AITD), 58, 257, 306 Autonomously functioning thyroid nodules advantages and disadvantages of treatments, 190 antithyroid drugs, 188 cost-effective management, 190 description, 169–170 follow-up, 190 radioiodine therapy, 189–190 surgery, 188 B Bexarotene, 746 Billewicz index, 396 Binding assays, 70–71 Biotin, 753 BRAF-directed therapy, 656 redifferentiation, 660 BRAF-mutant anaplastic carcinoma, 658 B-type rapidly accelerated fibrosarcoma oncogene (BRAF) point mutation, 568 C Cabozantinib, 615, 653 Calcitonin, 138, 600–602 Cancer, 497 Carbohydrate metabolism, 313 Carcinogenicity, 151 Carcinoma showing thymus-like differentiation (CASTLE) tumors, 638 Cardiovascular, 497 Central hypothyroidism causes, 375 characterization, 374 # Springer International Publishing AG, part of Springer Nature 2018 P Vitti, L Hegedus (eds.), Thyroid Diseases, Endocrinology, https://doi.org/10.1007/978-3-319-45013-1 763 764 Central hypothyroidism (cont.) clinical and biochemical presentation, 380–382 congenital forms, 376 etiopathogenesis, 374–380 prevalence, 374 treatment, 382–384 Cerebrovascular events, 497 Chemiluminescent assay, 43, 44 Chemotherapy, 631–632, 634 Childhood, 501 Cigarette smoking, 436 Cold thyroid nodules description, 170–172 percutaneous ethanol injection therapy, 192 surgery, 191 thyroid hormone treatment, 191 Computed tomography (CT), 92–93, 141 Congenital hypothyroidism (CH) classification, 335 definition, 334 diagnosis, 334, 349–353 diagnostic re-evaluation, 355–356 newborn screening, 334 outcomes, 356–359 peripheral, 347 primary, 336–345 secondary/central, 345–347 transient, 348–349 treatment and monitoring, 354–355 Consumptive hypothyroidism, 310 C-reactive protein (CRP), 281 Critical illness, 717, 722, 724, 725 Cyclosporine, 505 Cytotoxic agents, 744 Cytotoxic T-lymphocyte antigen-4, 432 D Dabrafenib, 657, 658, 660 Deiodinases, 711, 716–719 Denileukin diftitox, 747 De Quervain’s thyroiditis, 279, 285 Desiccated thyroid extract, 410 Diarrhoea, 618 Differentiated thyroid cancer, see Thyroid cancer Differentiated thyroid carcinoma clinial course, 572 diagnosis, 570–572 epidemiology, 564 follow-up, 578–581 Index kinase inhibitors, 585 pathogenesis, 568–570 pathology, 565–568 patient management, 580 prognostic factors, 573–574 radioiodine ablative therapy, 576–578 surgery, 575–576 Differentiation, 545, 552, 553 Diosmectite, 618 DOPA decarboxylase (DDC), 20 Dopamine, 735 Doxorubicin, 583 Dual oxidase (DUOX2), 10, 344 Dysthyroid optic neuropathy (DON), 505, 506 E Endocrine disruptors, 750, 751 Enhancer of zeste homolog, (EZH1), 522 Environment, 218, 221, 230, 233–237 Epidemiology, 217–224 Equilibrium dialysis, 39 Euthyroid autoimmune thyroid, 687–688 Euthyroid sick syndrome, 710 Everolimus, 661 Exacerbation of hyperthyroidism, 497 External radiation therapy, 630, 631, 634, 639 Extracellular domain (ECD), 69 Extrathyroidal complications, 74–75 F Familial dysalbuminemic hyperthyroxinemia, 38 Fetal thyroid gland, 677, 693, 696 Fine needle aspiration (FNA), 280, 281, 289–282 Fine-needle aspiration biopsy (FNAB), 143–144 Fine needle aspiration cytology (FNAC), 176–178, 570, 600, 633, 634, 637, 698 Flow volume loop, 142 Follicular carcinoma, 564, 566–567 Follicular neoplasia, 144 Free thyroid hormone index (FT4I), 40 Free thyroid hormone tests, 39–41 FT3 measurements, 35, 40, 41 FT4 measurements, 41 Functional assays, 71–72 Functional autonomy, thyroid nodules, 129, 133, 150 Index G Genetic polymorphisms, 227 Gestational diabetes mellitus (GDM), 256 Gestational transient thyrotoxicosis, 689 vs Graves’ disease, 690 GLIS3, 341 Glucocorticoids, 284, 285, 292–293, 735 Glucuronidation, 22 Goiter, 129, 515, 517, 522, 527 diagnosis, 135–137, 144 impact on oesophagus, 134 impact on trachea and respiratory function, 134 impact on voice, 135 iodine supplementation, 145 levothyroxine suppressive therapy, 145–146 multinodular, 141, 143, 156 nodular, 130–131, 133 nontoxic, 129, 147 prevalence, 132 shrinkage, 148–149 symptoms of, 133 types, 129 Graves’ disease (GD), 60, 525, 689, 691, 696, 700 antithyroid drugs for, 693 characteristics, 430 clinical presentation, 441 complications, 692 diagnosis, 691 epidemiology, 431 genetics, 431 HLA complex, 432 immunopathogenesis, 438 investigation and diagnosis, 442 management options, 692 outcomes, 692 pre-conception counselling, 697 symptoms and signs, 441 treatment, 444 Graves’ hyperthyroidism antithyroid drugs, 491 childhood, 501 immune reconstitution, 502 pregnancy, 500 radioiodine treatment, 496 subclinical hyperthyroidism, 502 therapeutic options for, 500 thyroidectomy, 498 thyroid storm, 503 Graves’ ophthalmopathy (GO), 59 765 Graves’ orbitopathy (GO), 479, 506 assessment, 470–471 cyclosporine, 478, 505 and cytokines, 457–458 differential diagnosis, 464–465 disease activity, 468–469 disease severity, 468 dysthyroid optic neuropathy, 506 epidemiology, 461–462 EUGOGO guidelines, 480 eye evaluation, 465–468 eyelids, surgical repair of, 482 factors, 454 first-line treatment, 504 general, anatomical and functional aspects, 459–460 glucocorticoids, 476–477 IgGs, 459 inactive eye disease, 479 lymphocytes and development, 458 management of, 473 mild GO, 474–475, 503 natural history, 471–472 ocular surface and tear film abnormalities, 460–461 orbital decompression, 481–482 orbital fibroblast, 454–457 orbital imaging, 470 orbital radiotherapy, 477–478, 504 progression/de novo development of, 498 quality of life, 470 rituximab, 478–479, 506 signs, 462–464 strabismus surgery, 482 symptoms, 462 TSHR, 459 VISA classification, 469–470 H Hashimoto’s thyroiditis, 59, 63, 207, 306 classification system, 217 diagnosis, 207–213 fibrous variant, 213 genes and environment, 230–237 goitre, 211 goitrous and atrophic variants, 215–216 hashitoxicosis, 217 histopathology, 208–210 history of, 207, 217 IgG4-related variant, 216 incidence, 221–224 juvenile thyroiditis, 217 766 Hashimoto’s thyroiditis (cont.) pathogenesis, 224–230 prevalence, 219–221 silent/painless thyroiditis and postpartum thyroiditis, 217 thyroid antibodies, 210–211 thyroid function, 211–212 thyroid ultrasonography, 212–213 Hepatotoxicity, 493 Heterophilic antibodies, 42 Highly active antiretroviral therapy (HAART), 744 Hook effect, 48, 49 Hormones, 437 Hot thyroid nodules, see Autonomously functioning thyroid nodules Human chorionic gonadotrophin (hCG), 675, 689–690 Human leukocyte antigen, 432 Hürthle cell carcinoma, 567 Hypercortisolism, 619 Hyperthyroidism, 7, 280, 284, 287–288, 515, 517, 523, 525, 528, 530, 533–518, 523–525 Hyperthyrotropinemia, 338 in childhood/adulthood, 340 definition, 335 Hypoadrenalism, 418 Hypophysiotropic TRH, Hypopituitarism, 378–379 Hypothalamic-pituitary-thyroid regulation drug interference, 735 Hypothyroidism, 682 algorithm for diagnosis, 398 causes, 682 classification, 304 clinical features, 311 definition, 302 epidemiology, 304–305 etiopathogenesis, 306 imaging, 405 management, 413 maternal hypothyroxinemia, 686 overt hypothyroidism (see Overt hypothyroidism) prevalence of symptoms and signs, 395–397 primary and secondary, 393 screening, 686–687 subclinical hypothyroidism, 684–685 thyroid hormone replacement, 405–406 thyroxine and triiodothyronine reference range, 401 treatment, 405–408 Index TSH, FT3 and FT4 397–399 TSH reference range, 398–399 Hypothyroxinemia, 677, 686 I IgG4-related disease (IgG4), 216–217 Interleukin-2 (IL-2) 747 Immune checkpoint-directed therapy, 664 Immune checkpoint inhibitors, 748 Immune reconstitution, 437 Immunoenzymatic assay, 45 Immunometric assays (IMA), 61 Immunopathogenesis, 217 Immunoradiometric assay, 43 Immunoregulatorydrugs, 747–749 Infectious thyroiditis, 280, 281 See also Acute infectious thyroiditis Inflammation, 460, 461, 469, 481 Inner ring deiodination (IRD), 17 Inositol, 751 Insular carcinoma, 567 Interference, 48 human anti-mouse antibodies, 49 Tg antibody, 48 Interferon alpha (IFN-α), 266, 742–744, 748 Intravenous glucocorticoids, 504 Iodine, 9, 436, 677, 678 daily intake, 681 deficiency, 130, 132, 157, 680–682 status, pregnant women, 681 supplementation, 681 Iodine-based cancer therapies, 746 Iodothyronines, 11 131 I radioiodine therapy, 134, 148–149, 526, 532 adverse effects, 149–151 concerns with, 151–152 effect on adjacent neck structures, 155–156 of nodular goiter, 150 recombinant human TSH (rhTSH) stimulation, 152–154, 156 Ischemic heart disease, 419 J Jagged, protein (JAG1), 341 Juvenile thyrotoxicosis, 523 K Kinase, 548, 555, 556 Kocher-Debre-Semelaigne (DKS) syndrome, 349 Index L L-carnitine, 752 Lenalidomide, 747 Lenvatinib, 652 Levothyroxine, 293, 406–408, 683–685 Levothyroxine sodium, 753 Levothyroxine suppressive therapy, 145 Levo-thyroxine therapy (LT4), 578 Liothyronine, 408 Lipid metabolism, 313 Lithium, 266–267, 737 Low T3 syndrome, 710 L-thyroxine, 382–383, 396, 409 Lymphoma, 636 M Magnetic resonance imaging (MRI), 92–93, 141 Mammalian target of rapamycin (mTOR)directed therapy, 661 inhibitor temsirolimus, 662 MAPK, see Mitogen activated protein kinases (MAPK) Markers of thyroid autoimmunity, 138 Maternal hypothyroxinemia, 686 Maternal thyroid hormones, 677, 678 Medullary thyroid cancer (MTC), 138, 606, 650 clinical presentation, 596–598 diagnosis, 600 pathogenesis, 592–596 prevalence, 591 MEK-directed therapy, 658–659 redifferentiation, 660 Multiple endocrine neoplasia type (MEN 2) syndromes, 619–620 Meta-iodobenzylguanidine (MIBG), 614 Metastatic disease, 581 chemotherapy, 583 external beam radiotherapy, 583 radioactive iodine therapy, 582 surgery, 582 Metformin, 740 Methimazole/carbimazole, 13, 491, 493, 693, 695, 700 Micronodular diffuse lung metastases, 583 Micropinocytosis, 12 Mitogen activated protein kinases (MAPK), 548, 552, 554, 655 Molecular diagnostics, 177, 180 Mucoepidermoid carcinoma, 637 Multinodular goiter, 129 Mutations, 168–169, 171, 180, 182–186 767 N Neck compression, 135, 145, 157 Neonatal thyrotoxicosis, 696–697 Neoplastic progression, thyroid carcinoma, see Thyroid carcinoma (TC) Newborn screening, 334 Non-autoimmune hyperthyroidism, 533 Non-invasive interventional therapy, 157 Non-thyroidal illness syndrome (NTIS), 710 acute and prolonged, 725–727 definition, 712 diagnosis, 713–715 etiology, 719–720 pathogenetic mechanisms, 715–716 pathophysiology, 716 prevalence, 727 TFT, 713 Non-toxic goiters, 129, 147 Nutraceuticals, 751 O Ophthalmopathy, 453 Orbital radiotherapy, 504 Outer ring deiodination (ORD), 17 Over-the-counter products, 751 Overt hypothyroidism, 682–683 diagnosis, 683 management, 683–684 outcomes, 683 P Papillary thyroid carcinoma incidence, 564 type, 565 variants, 566 Pendrin antibodies, 58, 77 Perchlorate discharge test, 9, 51 Percutaneous ethanol injection therapy, 192 Pernicious anemia, 418 Pertechnetate, 10 Pheochromocytoma, 619 PI3K/AKT pathway, 661 Piriform sinus tract fistula, 280–283 Plasma transport, 13 Plummer’s disease, see Toxic multinodular goiter (TMNG) Positron emission tomography (PET), 141 Postpartum thyroiditis (PPT), 68 clinical features of, 257–260 definition, 251 historical aspects, 252 incidence of, 252–253 768 Postpartum thyroiditis (PPT) (cont.) long term outcome of, 260–261 management of, 261 pathogenesis of, 253–255 risk factors, 255–257 screening for, 261–262 selenium, 262–263 Prednisolone, 292–293 See also Glucocorticoids Pregnancy, 62, 437, 500 See also Thyroid diseases in pregnancy Primary thyroid lymphoma, 636 Propylthiouracil (PTU), 491, 494, 496, 500, 693, 694, 696, 700 6-Propyl-2-thiouracil, 13 Protein bound iodine (PBI), 394 Protein kinase A (PKA), 522 Protein metabolism, 313 Protein tyrosine phosphatase, non-receptor type 22 (PTPN22), 433 Pyroglutamyl peptidase, Q Quality of life, 133, 135, 149, 154 R Radiation thyroiditis, 284 Radioactive iodine (RAI), 263, 284, 651 Radioimmunoassay (RIA), 39, 43, 61, 394 Radioimmunotherapy, 746 Radioiodine differentiated thyroid carcinoma, 576 metastatic disease, 582 treatment, 189, 496, 531 Rearranged during transfection (RET), 592–596, 663 Recombinant human thyrotropin (rhTSH), 152, 153, 577, 578 Regulatory CD4 + CD25 + T cells (TREG cells), 677 Response Evaluation Criteria in Solid Tumor (RECIST), 655 Retinoid X receptor (RXR), 22 Rexinoids, 736 Rifampin, 740 Risk assessment, 143, 150 Rituximab, 505 S Sarcoma, 638 Scintigraphy, 174–175 Sec-insertion sequence (SECIS), 18 Index Selective serotonin reuptake inhibitors (SSRIs), 739 Selenium, 751 Selumetinib, 658 Serum thyroglobulin, 138, 270 Serum thyrotropin, 41–45 Sialadenitis, 497 Smoking, 436 Sodium iodide symporter (NIS), 58, 76–77, 739 Somatostatin, 735 Sorafenib, 651–652 Spindle epithelial tumor with thymus-like elements (SETTLE) tumor, 639 Sporadic painless thyroiditis amiodarone, 267 clinical features, 268–269 definition, 263 differential diagnosis, 269–270 epidemiology, 263–264 hormonal factors, 265 interferon-α, 266 lithium, 267 management, 271 pathogenesis, 264–265 recurrent silent thyroiditis, 271–272 thyroid autoimmunity, 265 Squamous cell carcinoma, 633 Stress, 436 Subacute granulomatous thyroiditis, 279, 291 Subacute thyroiditis diagnostic evaluation, 288–291 differential diagnosis, 291–292 epidemiology, 286–287 pathogenesis, 285–287 presentation/clinical features, 287–288 treatment, 292–294 Subclinical hyperthyroidism, 502 Subclinical hypothyroidism, 304, 684 Sulfation, 21 Surgical treatment, 528 T Telomerase reverse transcriptase (TERT), 549, 554, 569 Teratogenicity, 151, 497 Teratoma, 633–634 TERT, see Telomerase reverse transcriptase (TERT) Tetraiodothyroacetic acid, 20 Thalidomide, 747 Thionamides, 491, 494, 495, 500, 501 Thyroglobulin (TG), 10, 47–49, 58, 345, 435, 440, 574, 576 Index Thyroglobulin antibodies (TG-Ab) antigen, 59–60 interference, 48 pathogenesis disease, 60–61 pregnancy, 62 thyroid autoimmunity, 61–62 thyroid cancer, 62–63 Thyroid ablation, 578 Thyroid abnormalities, 744 Thyroid antibodies, 288, 292 Thyroid-associated orbitopathy (TAO), 430 Thyroid autoimmunity, 61–62, 265–266 Thyroid autonomy, 517 Thyroid cancer, 62–63, 698–699 differentiated (see Differentiated thyroid carcinoma) incidence, 564 investigational drugs, 649 kinase inhibitors, 649 locally advanced/metastatic, 647 Thyroid carcinoma (TC), 646 anaplastic and poorly differentiated thyroid carcinoma, 553–555 classification of, 545–547 epidemiology of, 545 etiology of, 547–548 follicular thyroid carcinoma, 552–553 medullary thyroid carcinoma, 555–556 molecular pathogenesis of, 548–549 papillary thyroid carcinoma, 550–552 Thyroid dermopathy, 506 Thyroid diseases anaplastic thyroid carcinoma, 630–632 mucoepidermoid carcinoma, 637 primary thyroid lymphoma, 636 sarcoma, 638 SETTLE tumor, 639 thyroid teratoma, 634 Thyroid diseases in pregnancy assisted reproductive technology (ART), 688 euthyroid autoimmune thyroid, 687 fetal thyroid function, 677 hypothyroidism (see Hypothyroidism) iodine deficiency and consequences, 680 maternal thyroid physiology changes, 675 thyroid cancer, 698 thyroid function assessment, 679 thyroid hormone action, 677 thyroid nodules, 698 thyrotoxicosis (see Thyrotoxicosis) Thyroid dysgenesis (TD), 336, 341 Thyroid dyshormonogenesis, 342, 345 769 Thyroidectomy, 144, 146, 147, 149, 498 Thyroid function, 138 drug interference, 737, 740, 741 Thyroid hormone actions, 22–26, 680 antibodies, 77–78 biosynthesis, 8–13 binding proteins, 36, 38, 41 metabolism of, 17–22 transport of, 13–17 treatment, 191 Thyroid imaging computed tomography and magnetic resonance, 92–93 for diffuse thyroid disease, 93–96 malignancy, in focal thyroid leisons, 96–107 post-surgical thyroid, 116–117 pre-surgical staging, 107–115 role of, 91 ultrasonography, 91–92 uses, 90 Thyroid imaging reporting and data system (TIRADS), 140 Thyroid immunity, 66 Thyroid infiltration, 308 Thyroiditis, 278 classification, 279 Thyroid, 131I uptake measurement, 142 Thyroid nodules, 96–99, 104, 129, 139, 140, 698 benign, 132 co-existing autonomous, 149 detection, 131 functional autonomy, 129, 146, 150 non-invasive interventional treatments, 156 solitary, 130 ultrasonography, 140 Thyroid peroxidase (TPO), 58 antibodies, 682, 684, 685, 688, 700 gene, 344 Thyroid peroxidase antibodies (TPO-Ab), 256, 260 antigen, 64–65 autoimmune hypothyroidism, 66–67 infertility, 67–68 pathogenesis disease, 65 pregnancy, 67–68 thyroid immunity, 66 Thyroid scintigraphy, 140, 259 Thyroid sonography, 572 Thyroid stimulating hormone (TSH), 7–8, 58, 675, 679, 682, 684, 688, 691, 698 reflex, 45 770 Thyroid stimulating hormone receptor (TSHR), 58, 435, 520–523, 533–522 antigen, 69 thyroid autoimmunity, 69 Thyroid stimulating hormone receptor antibodies (TSHR-Ab) binding assays, 71 detection of, 70–71 extrathyroidal complications, 74–75 functional assays, 71–72 hyperthyroidism, 72–73 pathogenesis disease, 69–70 pregnancy, 75–76 Thyroid storm, 696 Thyroid surgery, 146–148 Thyroid teratoma, 634 Thyroid ultrasound, 96–105, 131, 139, 141 Thyrostimulin, Thyrotoxicosis, 689 anti-thyroid drugs for, 695–696 causes and pathogenesis, 689 factitiafrom, 752 gestational transient thyrotoxicosis, 689–691 Graves’ disease (see Graves’ disease) neonatal thyrotoxicosis, 696 thyroid storm, 696 Thyrotropin receptor antibodies (TRAb), 259, 288, 291, 691, 692, 696 Thyrotropin-releasing hormone (TRH), 5–7, 46 Thyroxine (T4), 35, 675, 676, 678, 682, 695 Thyroxine binding globulin (TBG), 675, 679 Toxic adenoma (TA), 515 antithyroid drugs, 528 biochemical and growth properties, 519 cAMP activation, 519 in children and adolescents, 523 clinical presentation, 515 diagnosis, 526 imaging techniques, 527 management algorithm, 527 non-autoimmune hyperthyroidism, 533 pathology, 518 percutaneous ethanol injection therapy (PEIT), 532 prevalence, 515 radiofrequency ablation (RFA), 532 radioiodine therapy, 531 signs and symptoms, 523, 524 surgical treatment, 530 treatment, 528 Index Toxic multinodular goiter (TMNG), 515 antithyroid drugs, 528 biochemical and growth properties, 519 cAMP activation, 519 in children and adolescents, 523 clinical presentation, 515 diagnosis, 526 imaging techniques, 527 non-autoimmune hyperthyroidism, 533 pathology, 518 percutaneous ethanol injection therapy (PEIT), 532 radiofrequency ablation (RFA), 532 radioiodine therapy, 531 signs and symptoms, 523 surgical treatment, 530 treatment, 528 TP53, 549, 554 Transthyretin (TTR), 13 Transthyretin-associated hyperthyroxinemia, 38 Traumatic thyroiditis, 284–285 T regulatory cells, 254 Tricyclic antidepressants, 739 Triiodothyroacetic acid, 20 Triiodothyronine (T3), 35, 312 TT3, 36 TT4, 36–37 Type, diabetes mellitus (T1DM), 256 Tyrosine kinase inhibitors (TKIs), 614, 650–618, 745 U Ultrafiltration, 39 Ultrasonography, 174 Urinary iodine, 35, 50 Urinary iodine concentration (UIC), 680 V Vandetanib, 615, 653 Vasculitis, 494 VEGFR-directed TKI therapy, 652 Vemurafenib, 657 Vitamin D deficiency, 438 W Wolff-Chaikoff effect, 12, 267 ... International Publishing AG, part of Springer Nature 20 18 P Vitti, L Hegedüs (eds.), Thyroid Diseases, Endocrinology, https://doi.org/10.1007/97 8-3 -3 1 9-4 501 3-1 _14 391 3 92 S Ashraff and S Razvi Assessing... Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroidstimulating hormone and thyroxine Acta Paediatr 20 02; 91:1 72 7 Bando H,... 3.0–3.49, 3.5–3.99, and 4.0–4.49 mU/L, respectively (Hollowell et al 20 02) Overall only 22 .2% of those subjects with TSH between 3.0 and 4.49 mU/L in the disease-free group had anti-TPO antibodies