Thyroid Research - Latest Articles

Effect of thyroid statuses on sodium/iodide symporter (NIS) gene expression in the extrathyroidal tissues in mice

Md. Harun-Or-Rashid — 2010-06-09T00:00:00Z

Background: Iodide that is essential for thyroid hormone synthesis is actively transported into the thyroid follicular cells via sodium/iodide symporter (NIS) protein in vertebrates. It is well known that NIS expression in thyroid is regulated by the thyroid statuses mainly through thyroid stimulating hormone (TSH). Although NIS mRNA expressions in extrathyroidal tissues have been qualitatively reported, their regulation by thyroid statuses has not been well clarified. Methods: Male ICR mice aged four weeks were assigned into three groups (control, hypothyroid, and hyperthyroid). Hypothyroid group of mice were treated with 0.02% methimazole in drinking water and hyperthyroid group of mice received intraperitoneal injection (4 μg L-T4 twice a week) for four weeks. NIS mRNA expression levels in the tissues were evaluated using Northern blot hybridization and quantitative real-time RTPCR (qPCR). Additionally, end-point RTPCR for the thyroid follicular cell-characteristic genes (TSH receptor, TSHR; thyroid transcription factor-1, TTF1; and paired box gene 8, Pax8) was carried out. Results: By Northern blot analysis, NIS mRNA was detected in thyroid and stomach. In addition to these organs, qPCR revealed the expression also in the submandibular gland, colon, testis, and lung. Expression of NIS mRNA in thyroid was significantly increased in hypothyroid and decreased in hyperthyroid group. Trends of NIS mRNA expression in extrathyroidal tissues were not in line with that in the thyroid gland in different thyroid statuses. Only in lung, NIS mRNA was regulated by thyroid statuses but in opposite way compared to the manner in the thyroid gland. There were no extrathyroidal tissues that expressed all three characteristic genes of thyroid follicular cells. Conclusions: NIS mRNA expression in the thyroid gland was up-regulated in hypothyroid mice and was down-regulated in hyperthyroid mice, suggesting that NIS mRNA in the thyroid gland is regulated by thyroid statuses. In contrast, NIS mRNA expression in extrathyroidal tissues was not altered by thyroid statuses although it was widely expressed. Lack of responsiveness of NIS mRNA expressions in extrathyroidal tissues reemphasizes additional functions of NIS protein in extrathyroidal tissues other than iodide trapping.

Thyroid function in children with growth hormone (GH) deficiency during the initial phase of GH replacement therapy - clinical implications

Joanna Smyczynska — 2010-03-22T00:00:00Z

Background: Normal thyroid hormone secretion or appropriate L-thyroxine (L-T4) substitution is necessary for the optimal effect of the growth hormone (GH) administration on growth rate. The decrease of free thyroxine (FT4) levels at recombinant human GH (rhGH) therapy onset has been reported in several studies. The aim of the present study was to evaluate the effect of rhGH administration on thyrotropin (TSH) and FT4 serum concentrations in children with GH deficiency (GHD) during the 1st year of therapy, as well as to assess potential indications to thyroid hormone supplementation in them.Patients and methodsThe analysis involved data of 75 children (59 boys, 16 girls) with disorders of GH secretion (GHD, neurosecretory dysfunction - NSD) and partial GH inactivity (inactGH), who were treated with rhGH for - at least - one year. In all the children, body height and height velocity (HV) were assessed before and after 1 year of therapy, while TSH, FT4, IGF-I and IGFBP-3 before treatment and after 3-6 months and 1 year of treatment. In the patients, who revealed hypothyroidism (HypoT), an appropriate L-T4 substitution was introduced immediately. The incidence of HypoT, occurring during the initial phase of rhGH therapy, was assessed, as well as its influence on the therapy effectiveness. Results: Before rhGH substitution, there were no significant differences in either auxological indices or TSH and FT4 secretion, or IGF-I concentration and its bioavailability among the groups of patients. During the initial 3-6 months of rhGH administration, a significant decrease of FT4 serum concentration, together with a significant increase of IGF-I SDS and IGF-I/IGFBP-3 molar ratio was observed in all the studied groups. In 17 children, HypoT was diagnosed and L-T4 substitution was administered. Despite similar IGF-I secretion increase, the improvement of HV presented significantly lower in children with HypoT than in those who remained euthyroid all the time. Conclusions: The incidence of HypoT during the initial phase of GH treatment in children with GHD and the negative effect of even transient thyroid hormone deficiency on the growth rate should be taken into account.

Acute myocardial infarction as the first presentation of thyrotoxicosis in a 31-year old woman - case report

Krzysztof Lewandowski — 2010-02-08T00:00:00Z

A 31-year old woman, previously fit & well was admitted with pressing retrosternal chest pain and palpitations of sudden onset. Her body weight was normal (BMI 20.5 kg/m2) and there was no significant family history of cardiac disease. She smoked, however, about 15 cigarettes a day and she had been taking combined oral contraceptive pill (Cilest®) for about three years. On admission she appeared sweaty and in pain, blood pressure 130/70 mmHg, heart rate about 110/min, mild lid-lag sign. Heart sounds were normal and chest was clear. ECG revealed 2-3 mm ST segment elevations in II, III, aVF as well as V2 to V5. Troponin I was raised and she was qualified to an emergency coronary angiography. This revealed a massive spasm of left anterior descending (LAD) coronary artery that responded to intracoronary glyceryl trinitrite administration, however, with the presence of critical narrowing of the LAD apical segment with possible superimposed thrombus. Cardiac ultrasound revealed akinesis of 1/2 of apical area consistent with myocardial infarctionTreatment and progressShe was started on Aspirin, Simvastatin, and Diltiazem, but continued to have persistent tachycardia and tremor. Thyroid function tests were ordered and showed thyrotoxicosis [free T4-46.9 pmol/l (ref. range 9-25), free T3-11.9 pmol/l (2-5), TSH - 0.02 mIU/l (0.27-4.2)]. She was referred for an endocrine opinion and started on Thiamazole. Other investigations revealed elevated anti-TPO and anti-TSH receptor antibodies consistent with Graves' disease. Thrombophilia screen was negative. She had remained euthyroid on a "block & replace" regimen (Thiamazole plus L-Thyroxine) that was discontinued after 18 months. She denies any anginal symptoms, but continues to smoke against medical advice. Conclusions: Our case highlights the possibility of development of an acute myocardial infarction in a young subject with thyrotoxicosis. We speculate that patient's smoking habit combined with subtle thyrotoxicosis-induced prothrombotic state and/or coronary-artery spasm had lead to the above-mentioned acute coronary event.

The influence of hepatitis C infection and interferon-alpha therapy on thyrotropin blocking and stimulating autoantibodies in Graves' ophthalmopathy: a case report

Huy Tran — 2009-12-02T00:00:00Z

Background: Hepatitis C virus is a highly immunogenic pathogen often inducing autoimmune activation changes and this can often be further exacerbated by Interferon therapy. As HCV is lymphocytotropic, it can modulate T cell and B cell antibody responses, affecting many endocrine organs, most commonly the thyroid.Case presentationWe hereby describe a case of fluctuating and wavering thyrotropin autoantibodies of both stimulating and blocking nature in the setting of Graves's ophthalmopathy, hepatitis C infection and interferon-α, causing hypo- and subsequently hyper-thyroidism. The autoantibody profile was clearly modified during interferon therapy and settled into a new equilibrium at the completion of treatment. Conclusion: The case highlights the possible existence of a dual thyroid autoantibody population associated with hepatitis C, and its modulation by interferon therapy, which further compounds the difficulties in the assessment thyroid disease in this setting.

Congenital leptin deficiency and thyroid function

Gilberto Paz-Filho — 2009-11-04T00:00:00Z

Thyroid function is closely related to leptin's secretion by the adipose tissue. In states of leptin-deficiency, the circadian rhythm of TSH is altered, leading to central hypothyroidism in animal models. In humans, central hypothyroidism has also been described in rare cases of congenital leptin deficiency. However, the thyroid phenotype in these cases is heterogeneous, with the occurrence of central hypothyroidism in a minority of cases. Here we describe thyroid function in four leptin-deficient humans (2 males aged 5 and 27, and 2 females aged 35 and 40), before and during leptin replacement with recombinant human methionyl leptin (r-metHuLeptin). The child was evaluated for four years, and the adults, for eight years. In addition, the adults were submitted to a brief withdrawal of leptin during six weeks in the sixth year. Our results show that, regardless of leptin replacement, our leptin-deficient patients have normal thyroid function. In spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function.Trial RegistrationClinicalTrials.gov Identifiers: NCT00659828 and NCT00657605

Association of polymorphism in genes encoding kappa B inhibitors (IkappaB) with susceptibility to and phenotype of Graves' disease: a case-control study

Alina Kurylowicz — 2009-11-03T00:00:00Z

Background: Genes related to the nuclear factor-κB (NF-κB), a key transcription factor involved in regulation of immune responses, are interesting candidates for association studies in autoimmune disorders. The aim of this study was to investigate an association of polymorphisms in two genes encoding NF-κB inhibitors: IKBL (encoding inhibitor of κB-like) and NFKBIA (encoding κB inhibitor α), withsusceptibility to and phenotype of Graves' disease (GD). Methods: A population-based, case-control association study comprising 481 patients with GD and 455 healthy controls was performed. We analyzed 3 single nucleotide polymorphisms (SNPs) in IKBL [promoter region -62T/A substitution (rs2071592), intron 1 C/T substitution (rs2071591) and exon 4 T/C substitution (rs3130062)] and 3 SNPs in NFKBIA [G/A substitution in 3' untranslated region (rs696) and two promoter region polymorphisms -297C/T (rs2233409) and -826C/T (rs2233406)] by the PCR-restriction fragment length polymorphism (RFLP) method. Results: The two SNPs in IKBL (rs2071592 and rs2071591) were in a strong linkage disequilibrium (D' = 0.835) and the AT haplotype was associated with susceptibility to GD (p < 10-4, OR = 1.61 [95%CI:1.21-2.14]). Moreover subgroup analysis revealed a gen-gen interaction between the investigated IKBL haplotype and HLA-DRB1*03 allele (p < 10-4). The investigated NFKBIA SNPs were not associated with susceptibility to GD. However, when correlated with phenotype, the -297T (rs2233409) and -826T (rs2233406) alleles were associated with the development of clinically evident ophthalmophaty (p = 0.004, pc = 0.07, OR = 1.65 [95%CI: 1.18-2.38] and p = 0.002, pc = 0.036, OR = 1.67 [95%CI: 1.20-2.36], respectively). Conclusion: Our results suggest that SNPs in genes encoding NF-κB inhibitors may contribute to the development and clinical phenotype of GD.

A minute focus of extranodal marginal zone B-cell lymphoma arising in Hashimoto thyroiditis diagnosed with PCR after laser capture microdissection: a case report

Antonio D'Antonio — 2009-09-07T00:00:00Z

Background: Primary thyroid gland lymphomas are uncommon tumours that occur in the setting of lymphocytic thyroiditis or Hashimoto's disease in almost all cases. In this condition a distinction between an inflammatory lymphoid infiltrate and a low grade lymphoma may be extremely difficult and precise criteria are necessary for a correct diagnosis.Patient and methodsWe report a case of a minute focus of primary extranodal marginal zone B-cell lymphoma (EMZBCL), incidentally discovered in a 63-year-old man with Hashimoto thyroiditis (HT) and diagnosed by means of polymerase chain reaction (PCR) after laser capture microdissection.The histological examination of surgical specimen confirmed the diagnosis of HT and showed a minute focus of dense lymphoid infiltrate (less than 4 mm in diameter), composed by centrocyte-like cells forming MALT balls. Immunoistochemistry was not useful. A microscopic focus of EMZBCL was suspected on the basis of morphological features. PCR assays revealed the rearrangement of the heavy chain of immunoglobulins only in the microdissected suspicious area, confirming the diagnosis of EMZBCL. Conclusion: Our finding suggests that in cases of autoimmune thyroiditis a careful examination of the thyroid specimen is warranted, in order to disclose areas or small foci of lymphomatous transformation. Furthermore, in difficult cases with doubtful immunohistological findings, ancillary techniques, such as molecular studies, are necessary for a conclusive diagnosis.

13-cis-retinoic acid re-differentiation therapy and recombinant human thyrotropin-aided radioiodine treatment of non-functional metastatic thyroid cancer: a single-center, 53-patient phase 2 study

Daria Handkiewicz-Junak — 2009-08-01T00:00:00Z

In 30–50% of patients with metastatic non-medullary thyroid cancer the metastases are not radioiodine-avid and so there is no effective treatment. Retinoids have demonstrated inhibition of thyroid tumor growth and induction of radioiodine uptake. The aim of our study was to assess benefits of the retinoic acid (RA) treatment to re-differentiate non-functional NMTC metastases.Patients and MethodsIn this prospective study, 53 patients with radioiodine non avid metastatic disease (45) or hyperthyroglobulinemia (8) were treated with 13-cis-retinoic acid (13-CRA) [1.0 mg/kg/day over 1st week and then 1.5 mg/kg] for six weeks prior to I-131 treatment performed under rhTSH stimulation. The re-differentiating effect of RA was evaluated by serum thyroglobulin (Tg) monitoring before and after cessation of RA treatment and by qualitative analysis of iodine uptake on the post-therapeutic whole body scan (rxWBS). Results: 13-CRA induced radioiodine uptake in 9 (17%) of patients. In the univariate analysis neither the patient's gender, age, tumor histopathology, uptake in thyroid bed nor time since thyroid cancer diagnosis was associated with results of rxWBS.41 (77%) patients were evaluable for Tg response before and after to 13-CRA treatment. There was a statistically significant increase in median Tg level (60 v. 90 ng/ml, p < 0.05). There was no difference in Tg increase between scintigraphic responders and non-responders.13-CRA and RIT was repeated at least once in 8 of 9 scintigraphic responders. None of them showed tumor regression by radiological imaging within 12 months after the first treatment, 4/9 (44%) of them had disease progression.13-CRA treatment was well-tolerated. All but one patient complained of at least one side effect the most prevalent being lip dryness (98%). All side effects were transient and resolved within 2 weeks after 13-CRA cessation. Conclusion: Our results show that in patients with non-functional metastases from NMTC, 13-CRA is able to exert some re-differentiation effect by induction of radioiodine uptake in <20% of patients and increase of Tg serum level in about 30% of them. Nevertheless, this does not transfer into clinical benefit as it neither induces measurable tumor response nor prevents disease progression.

Evaluation of selective embolization of thyroid arteries (SETA) as a preresective treatment in selected cases of toxic goitre

Marek Dedecjus — 2009-07-31T00:00:00Z

Background: in recent years, an increasing interest in the application of selective embolization of thyroid arteries (SETA) in the treatment of thyroid diseases is observed. In the present report, we analyse the value, safety and possible indications for preresective SETA in cases of large toxic goitres.Patients and methodthe study group comprised 10 patients with large toxic goitre (thyroid volume 254 ± 50 mL), including one patient with cervicomediastinal goitre and one patient with anti-thyroid drug intolerance in state of overt thyrotoxicosis. All the patients underwent SETA of the superior and/or inferior thyroid arteries, followed by thyroidectomy, performed up to thirty-six hours after SETA (23.1 ± 11 h). After embolization, selective angiographies of thyroid arteries were performed to ensure that the targeted arteries had been completely occluded.Results and conclusionin all the patients, SETA decreased blood flow through the thyroid. Preresective SETA reduced blood loss during and after thyroidectomy and decreased the operating time, but the differences were too small to justify routine applications of preresective SETA as an adjunct to surgical treatment of toxic goitre. On the other hand, SETA is a safe and minimally-invasive technique, which may become an attractive option for quick preparation to surgery in selected patients with toxic goitre, who present anti-thyroid drug intolerance or refuse radioactive iodine treatment.

Long-term outcome of low-activity radioiodine administration preceded by adjuvant recombinant human TSH pretreatment in elderly subjects with multinodular goiter

Massimo Giusti — 2009-06-30T00:00:00Z

Background: Large multinodular goiter (MNG) in elderly people is a common finding which can require intervention. The long-term effect of radioiodine therapy on thyroid volume (TV) and function after recombinant human (rh) TSH pre-treatment was evaluated. Methods: After baseline evaluation, 40 subjects over 60 years old with a large MNG were treated with 131I up to the activity of 600 MBq. Nineteen patients were pretreated with rhTSH (0.1 mg on 2 consecutive days; group 1) while 21 subjects underwent treatment without rhTSH pretreatment (group 2). TV was monitored every 6–12 months by ultrasonography. The median follow-up period was 36 months. Results: At the baseline, the groups matched in terms of TV, 24-h radioiodine uptake (RAIU), urinary iodine and neck complaints. The number of subjects pretreated with anti-thyroid drugs was significantly (P = 0.01) greater in group 2 than in group 1; TSH was more suppressed (P = 0.003) and f-T3 was more elevated (P = 0.005) in group 2 than in group 1 patients. RhTSH increased 24-h RAIU in group 1 up to the baseline level observed in group 2. The 131I activity administered was similar in both groups. Adverse events were slight and similar in both groups. A permanent post-radioiodine toxic condition was reported only in 2 patients in group 2. After radioiodine therapy, hypothyroidism was observed in significantly more group 1 patients than group 2 patients (P = 0.002). While TV was reduced in both groups, the percentage TV reduction recorded at the last examination was significantly higher (P = 0.03) in group 1 than in group 2. MNG-related complaints were significantly reduced in both group 1 (P = 0.0001 vs baseline) and group 2 (P = 0.001) patients. Conclusion: Low radioiodine activities after pretreatment with low-dosage rhTSH are able to reduce TV and improve MNG-related symptoms in elderly subjects.