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Concept: Hashimoto's thyroiditis

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Background The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. Methods We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). Results The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. Conclusions Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

Concepts: Clinical trial, Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid hormone, Placebo

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The endocrine system and particular endocrine organs, including the thyroid, undergo important functional changes during aging. The prevalence of thyroid disorders increases with age and numerous morphological and physiological changes of the thyroid gland during the process of aging are well-known. It is to be stressed that the clinical course of thyroid diseases in the elderly differs essentially from that observed in younger individuals, because symptoms are more subtle and are often attributed to normal aging. Subclinical hypo- and hyperthyroidism, as well as thyroid neoplasms, require special attention in elderly subjects. Intriguingly, decreased thyroid function, as well as thyrotropin (TSH) levels – progressively shifting to higher values with age – may contribute to the increased lifespan.This short review focuses on recent findings concerning the alterations in thyroid function during aging, including these which may potentially lead to extended longevity, both in humans and animals.

Concepts: Thyroid disease, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Graves' disease, Endocrine system, Triiodothyronine

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Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto’s thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.

Concepts: Bioinformatics, Single-nucleotide polymorphism, Thyroid disease, Genetic genealogy, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Minor allele frequency

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C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF-Tshr(hyt/wild) heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshr(hyt/wild) mice are smaller than those from wild-type mice, and (125)I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co-transfected into HEK 293 cells, the cells retained (125)I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshr(hyt/wild) mice.

Concepts: DNA, Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid hormone, Förster resonance energy transfer, HEK cell

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Congenital hypothyroidism, usually of the primary and permanent variety, is an eminently preventable cause of growth retardation and mental handicap whose outlook has been transformed by newborn screening, usually involving the measurement of capillary TSH. Severe primary congenital hypothyroidism, due for example to athyreosis, may result in subtle cognitive, behavioural and sensori-motor deficits, but the extent to which these can be offset by optimal postnatal diagnosis and management remains uncertain. This is because the available adult follow-up data reflect the outcome of previous management in the 1970’s and 1980’s, and also because the accurate neuro-psychological assessment of children is difficult, particularly in the preschool population. There is an urgent need to develop new consensus guidelines and to ensure that the children managed according to such guidelines are systematically and prospectively assessed so that good quality outcome data become available. In this review, key recommendations in the management of congenital hypothyroidism include: screening at day 3 so that severely affected infants can begin treatment within the first 10 days of life; setting the thyrotropin (TSH) referral cut-off at 8-10 mU/L; adopting a disciplined diagnostic algorithm to evaluate referred cases, with measurement of venous free thyroxine (T4), TSH and thyroglobulin combined with dual ultrasound and radioisotope imaging; initial treatment with a T4 dose of 50 μg daily in infants weighing ≥ 2.5 kg and 15 μg/kg/day in infants weighing < 2.5 kg followed by weekly review until thyroid function is normalised; and maintenance of free T4 levels between 15-26 pmol/L and TSH between 0.5-5 mU/L thereafter to avoid both under- and overtreatment.

Concepts: Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Thyroid, Thyroid hormone, Thyroxine, Newborn screening, Congenital hypothyroidism

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OBJECTIVE: To identify the clinical findings of Hashimoto’s encephalopathy (HE) in children and assess their neurological outcome. METHODS: In this retrospective observational study of 42 children with encephalitis dominated by acute neuro-behavioral features, eight met the diagnostic criteria of HE. Their biological, EEG and brain MRI characteristics were compared to those of the other 34 children. Their clinical outcome was also compared to that of 14 children with Hashimoto’s thyroiditis (HT). RESULTS: All eight HE children were girls and had high levels of anti-thyroid peroxidase (TPO) antibodies at onset (4043.3 ± 2969.8 IU/mL, inclusion criteria: TPO > 60 IU/mL) despite normal T4 and TSH levels in six of them. All HE children had abnormal EEG and brain MRI was abnormal in four of them. Relapses were observed in five children with a second relapse, despite steroid therapy, occurring sooner after the previous episode (median 18 days (range 17-188) vs 213 days (range 14-518)). Immunosuppressive therapy was started in all five children and two developed sequelae by the last follow-up visit (after 4 ± 1.3 years). Mean anti-TPO antibody titers were significantly higher in HE children than in those with Hashimoto’s thyroiditis (HT) (4043.3 ± 2969.8 IU/mL vs 1980.9 ± 3449.9 IU/mL, p = 0.03). Four HE children subsequently developed hypothyroidism whereas only one HT patient presented encephalitis. CONCLUSION: HE is characterized by suggestive clinical symptoms with high levels of anti-TPO antibodies and, in most cases, normal T4 and TSH titers. Despite steroid treatment, relapses and sequelae are frequent. HE may evolve toward HT, but the reverse appears to be rare.

Concepts: Observational study, Thyroid-stimulating hormone, Electroencephalography, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Immunosuppressive drug, Hashimoto's encephalopathy

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Background: The role of viruses as environmental triggers for Hashimoto’s thyroiditis (HT) is controversial. Thyroid epithelial cells express a variety of molecules involved in antiviral responses. This study combined histological, immunological and virological tests to describe changes in tissue from patients with newly diagnosed and untreated HT. To study the early events, patients with positive thyroid peroxidase antibodies (TPO-Ab) and normal thyroid function were also included. This stage was defined as “prethyroiditis”. Methods: Thyroid tissue was collected from 47 patients with high titers of TPO-Ab and from 24 controls. Seventeen patients had prethyroiditis, 17 had subclinical hypothyroidism, and 13 had overt hypothyroidism. IFN-α/β-inducible myxovirus resistance protein 1 (Myxovirus resistance protein A; MxA) was used as a surrogate marker for type I interferon (IFN) expression. Inflammation, expression of MxA, and the presence of the enteroviral capsid protein VP1 (VP1) were characterized by immunohistochemistry. The presence of enterovirus RNA was examined by in situ hybridization. Results: The density of CD4+ T cells was increased in all three patient groups, while CD8+ T cells were increased only in patients with overt hypothyroidism. The density of plasma cells increased as the disease progressed. The density of plasmacytoid dendritic cells (PDCs) and the expression of MxA were significantly increased in all patient groups compared with controls (p<0.01). Enterovirus RNA was present in 11% of HT patients but in none of the control subjects, whereas enteroviral protein was detected in 19% and 16%, respectively. Conclusion: The inflammatory reaction in the thyroid gland is a very early event in pathogenesis of HT. Increased expression of MxA in the inflamed tissue suggests that type I interferon plays a role in disease development. Whether this is virus-dependent needs to be explored in further studies.

Concepts: Immune system, Virus, Thyroid disease, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid peroxidase

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Objectives: Immunoglobulin (Ig)G4-related disease is a recently proposed systemic disorder that includes autoimmune pancreatitis (AIP), Mikulicz’s disease, and various other organ lesions. In the present retrospective study, we examined whether thyroid lesions should also be included in IgG4-related disease (Ig4-RD) under the new term IgG4-related thyroiditis. Method: We enrolled 114 patients with Ig4-RD, including 92 patients with AIP, 15 patients with Mikulicz’s disease, and seven patients with IgG4-related cholangitis, and analysed clinical findings, function, serum values of activity markers, computed tomography (CT) images, and histology of the thyroid gland. Results: Among the 22 patients (19%) in our cohort who were found to have hypothyroidism [thyroid stimulating hormone (TSH) > 4 mIU/L], 11 patients had clinical hypothyroidism [free thyroxine (FT4) < 1 ng/dL] and 11 patients had subclinical hypothyroidism (FT4 ≥ 1 ng/dL). Serum concentrations of IgG, IgG4, circulating immune complex (CIC), and β2-microglobulin (β2-MG) were significantly higher in the hypothyroidism group compared with the remaining 92 euthyroid patients, and serum C3 concentration was significantly lower. After prednisolone treatment, TSH values had decreased significantly (p = 0.005) in this group and FT4 values had increased significantly (p = 0.047). CT images showed that the thyroid glands of patients with clinical hypothyroidism had a significantly greater volume than those of the euthyroid and other groups. Pathological analysis of one resected thyroid gland disclosed a focused lesion with infiltration of lymphocytes and IgG4-bearing plasma cells and loss of thyroid follicles. Conclusions: Thyroid lesions associated with hypothyroidism can be considered as a new disease termed IgG4-related thyroiditis. Awareness of this condition should lead to appropriate corticosteroid treatment that may prevent progression to a fibrous state.

Concepts: Immune system, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid hormone, Triiodothyronine, Thyroxine

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Context:In recent years changes in screening strategies for congenital hypothyroidism (CH) led to an increased detection of mild forms of CH, associated with eutopic thyroid gland.Objectives:We aimed to determine the clinical evolution of CH with eutopic thyroid gland and to find out prognostic factors at diagnosis and follow-up.Patients and Methods:We retrospectively analyzed a group of 84 children with CH and eutopic thyroid gland treated at our institution. They all underwent clinical re-evaluation after the age of 3, based on thyroid function testing after l-thyroxine therapy withdrawal, thyroid ultrasonography, and (123)I scintigraphy with perchlorate discharge test. Genetic analysis was performed in selected cases.Results:At re-evaluation, 34.5% of patients showed permanent hypothyroidism and needed l-thyroxine reintroduction, 27.4% had persistent hyperthyrotropinemia (TSH 5-10 mU/L), and 38.1% had transient hypothyroidism. Major risk factors for permanent CH were prematurity, first-degree familial history of goiter/nodules, thyroid hypoplasia at diagnosis, and high l-thyroxine requirements at follow-up. Iodine organification defects were found in 29.7% of patients, 30% of whom harbored DUOX2 mutations. TSH receptor gene mutations were found in 8.7% of patients with persistent thyroid dysfunction and negative perchlorate discharge test.Conclusions:Only one-third of patients with CH and eutopic thyroid gland needed to continue l-thyroxine therapy after re-evaluation. A frequent finding was the persistence of mild hyperthyrotropinemia. The evolution of CH remains difficult to predict, although different clinical features might suggest different outcomes. Mutations in the genes commonly linked to mild forms of CH were documented in a minority of cases.

Concepts: Thyroid disease, Hypothyroidism, Hashimoto's thyroiditis, Thyroid, Thyroid hormone, Iodine, Endocrine system, Congenital hypothyroidism

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Background: Thyroid autoimmunity (TAI) is frequent in infertile women but to what extend thyroglobulin antibodies (Tg-Abs) contribute to TAI is unclear in literature. The aims of the present study were to determine the prevalence of TAI in women consulting for fertility problems and to investigate the impact of isolated Tg-Abs, isolated thyroid peroxidase antibodies (TPO-Abs) and the presence of both Ab types on thyroid function. Furthermore, thyroid function was compared between women with - and without TAI and between infertile and fertile women. Methods: Cross-sectional data analysis nested within an ongoing prospective cohort study, to determine the prevalence of TAI in unselected women consulting our tertiary referral center for reproductive medicine (CRM). The women underwent a blood sample for the determination of serum TSH, FT4, TPO-Abs and Tg-Abs. Cause of infertility, age, BMI and smoking habits were recorded. Results: The prevalence of TAI was 16% (163/992); in 8% both types of antibodies were present, in 5% of women isolated positive Tg-Abs were found and 4% had isolated positive TPO-Abs (p=0.025 and p=0.003, respectively). The prevalence of TAI was significantly higher in infertile women as compared to that in fertile controls (19% versus 13%; p=0.047). The median serum TSH level was significantly higher in the women with TAI and with isolated positive Tg-Abs, compared to that in women without TAI (1.83 [1.44] and 1.90 [0.85] versus 1.47 [0.94] mIU/L; p<0.001 respectively). The median FT4, age, BMI and smoking habits, were comparable between the study groups. Conclusions: The prevalence of TAI was higher in infertile women as compared to fertile women consulting our CRM. Five percent of the women had isolated positive Tg-Abs and a significantly higher serum TSH compared to that in women without TAI.

Concepts: Pregnancy, Infertility, Fertility, Hashimoto's thyroiditis, Thyroid, Assisted reproductive technology, Thyroglobulin, Thyroid peroxidase