Thyroid Disturbances Research Articles

The multiple effects of thyroid disorders on bone and mineral metabolism.

Differently from most hormones, which commonly are specialized molecules able to influence other cells, tissues and systems, thyroid hormones (TH) are pleiotropic peptides, whose primordial function is difficult to identify. The complex action of TH on human economy can be easily witnessed by examining the diverse consequences of TH excess and deficiency during development and after maturity. In particular, different manifestations in bone modeling and remodeling reflect the circumstantial consequences of thyroid disturbances, which are age dependent. While hyperthyroidism during childhood enhances bone mineralization and accelerates epiphyseal maturation, in adults it induces bone loss by predominant activation of osteoclast activity. Furthermore, the syndrome of TH resistance is a multifaceted condition in which different sites exhibit signs of hormone excess or deficiency depending on the configuration of the TH receptor isoform. The investigation of the impact of TH resistance on the skeleton still remains to be elucidated. We present here a thorough review of the action of TH on bone and of the impact of thyroid disorders, including hyper- and hypothyroidism and the syndrome of TH resistance, on the skeleton.

Detection of five substitution TPO mutations in Polycystic Ovary Syndrome (PCOS) and thyroid hormones disturbance patients

Polycystic ovary syndrome (PCOS (is a complex disorder which reflects variable clinical symptoms. There is considerable heterogeneity of symptoms and signs among women with PCOS, and for an individual, these may change over time. The genetic base of PCOS is not clear and no concrete genetic correlation was built with PCOS. The current study showed the presence of multiple peripheral small cysts 5-9 mm also there was an increase in ovarian volume 3.7-3.9 cm and change in ovarian dimensions with the ovary being more spherical. 20.8% of the PCOS patients included in this study found to have hyperthyroidism. Thethyroid stimulating hormone-TSH level was significantly higher 17.34±5.12μIU/ml in 4 POCS patients with thyroid hormones disturbance than the level in POCS patients without thyroid disturbance or healthy control group )2.19 ±0.47 and 2.33±0.44 μIU/ml respectively(. On the other hand, the rest of POCS patients with thyroid hormones disturbance 7 Patients showed lower significance levels of triiodothyronine-T3 and thyroxine-T4 (0.96±0.029 and 51.33± 10.96 n.mol/L respectively) than other groups. At the molecular analysis five substitution thyroid peroxidase genes -TPO mutations were detected in 5 patients with PCOS and thyroid hormones disturbances. Three of them were detected in exon 8 and two in exon 9. The missense substation mutations detected in this study involve one transition of T to C (c.904T>C) and 4 transversion of C to G, C to A and G to C (c.904T>C, c.1280C>G, c.1265C>A, c.1617G>C and c.1603G>C respectively).

Association pernicious anemia and autoimmune thyroiditis: A case-report and review of literature

Pernicious anemia was first described by Thomas Addison in 1849, anemia has been linked to stomach by Austin Flint in 1860 [1]. A woman aged 85 years, was admitted for investigation of anemia discovered incidentally. She was followed for type 2 diabetes, hypertension, dyslipidemia and rectal adenocarcinoma surgery. Clinical examination found a mucocutaneous pallor. The hemoglobin level was 7.3 g/dL, a mean corpuscular volume to 86 microns, platelets 350 000, reticulocyte 83 giga/L, prothrombin time 81%. This assessment of anemia was supplemented by iron status, which turns normal and vitamin status indicating a vitamin B12 deficiency estimated at 108 pg/mL, without vitamin B9 deficiency. We are in the presence of a regenerative normocytic anemia with vitamin B12 deficiency. Positivity of anti-intrinsic factor antibodies and parietal cell antibodies, and an increased gastrin. The diagnosis of pernicious anemia was confirmed by gastroesophageal gastroduodenal endoscopy; on a macroscopic level, an atrophic fundus lesion with hummocky was found, whose biopsies confirmed the appearance of atrophic gastritis with enterochromaffin-like cell hyperplasia. On the metabolic level, we noted the presence of a disturbed thyroid function with increased TSH. Positivity of anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies, which reveal the presence of autoimmune thyroiditis; it is also reinforced by the thyroid ultrasound finding an aspect of autoimmune thyroiditis consistent with Hashimoto’s thyroiditis. The rest of the immunological balance did not find others autoimmune diseases such as Sjogren disease, or autoimmune diabetes. Therefore, we are faced with a patient with the association of pernicious anemia and Hashimoto’s thyroiditis.

Triiodothyronine and breast cancer.

The thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), are essential for survival; they are involved in the processes of development, growth, and metabolism. In addition to hyperthyroidism or hypothyroidism, THs are involved in other diseases. The role of THs in the development and differentiation of mammary epithelium is well established; however, their specific role in the pathogenesis of breast cancer (BC) is controversial. Steroid hormones affect many human cancers and the abnormal responsiveness of the mammary epithelial cells to estradiol (E2) in particular is known to be an important cause for the development and progression of BC. The proliferative effect of T3 has been demonstrated in various types of cancer. In BC cell lines, T3 may foster the conditions for tumor proliferation and increase the effect of cell proliferation by E2; thus, T3 may play a role in the development and progression of BC. Studies show that T3 has effects similar to E2 in BC cell lines. Despite controversy regarding the relationship between thyroid disturbances and the incidence of BC, studies show that thyroid status may influence the development of tumor, proliferation and metastasis.

Effect of Pioglitazone on Thyroid Hormones and IGF-I in Patients with Type 2 Diabetes

Background: Thyroid hormones induce insulin resistance. Pioglitazone is a peroxisome proliferator activated receptor gamma (PPARγ) agonist, used as treatment of type 2 diabetes (T2D) to increase insulin sensitivity. PPARs and thyroid hormone receptors (TRs) induce intracellular effects through similar molecular mechanisms, and the former may inhibit activation of the latter. Pioglitazone has been shown to increase eye protrusion, a symptom linked both to disturbed thyroid hormone levels and orbital edema secondary to increased IGF-I. Aims: We investigated whether attenuation of insulin resistance with pioglitazone affects thyroid hormone status and IGF-I. Methods: 48 patients with T2D were treated with pioglitazone for 26 weeks. Thyroid hormones and IGF-I were analyzed before and after treatment. Results: After treatment, decreased free T4 decreased (from 14.2+0.4 to 13.3+0.3 pmol/L, p=0.009) and TSH increased (from 190+200 to 220+200 U/L, p = 0.004). IGF-I also increased (from 0.5 ± 0.2 to 1.0 ± 0.2 SD, p<0.001). Conclusion: Pioglitazone lowers free T4 and increases IGF-I in T2D. This may be due to impeded activation of the TR due to PPAR activation. Increased TSH is most likely secondary to reduced T4. Increased IGF-I may cause orbital edema, as previously noted in patients treated with pioglitazone.

COPD and Thyroid Dysfunctions

Chronic obstructive pulmonary (COPD) is one of the major causes of morbidity and mortality in the world. COPD is characterized by chronic inflammation in the pulmonary compartment and in the systemic circulation. This disorder is associated with clinically significant alterations in biochemistry and organ function; thyroid dysfunctions are common in chronic diseases, such as COPD. Several characteristics of COPD patients could increase their likelihood of developing hypothyroidism or hyperthyroidism. The purpose of our study was to assess the impact of thyroid dysfunction in patients with COPD. We evaluated the pulmonary function tests, arterial blood gases, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and thyroid functions in patients with COPD, recruited between admissions in Respiratory Diseases Unit, Policlinico Umberto I, Rome, Italy, from June 2012 to May 2013. We selected patients with subclinical hypothyroidism (ScH), overt hypothyroidism, and hyperthyroidism, and a control group without thyroid disturbance. Our results indicate that patients with overt hypothyroidism have lower levels of pO2, MIP, and MEP compared with subjects with ScH, hyperthyroidism, and the control group. We also found a substantial tendency towards pCO2 levels increase in patients with hypothyroidism (p=0.06). Patients with thyroid dysfunctions have a greater impairment of MIP and MEP and a negative correlation was observed between hypoxemia and TSH. Further studies are needed to investigate whether the treatment of thyroid disfunction could have a beneficial effect on COPD patients' lung function and prognosis.

Thyroid Hormone Status and Health-Related Quality of Life in the LifeLines Cohort Study

Thyroid disorders are prevalent in Western society, yet many subjects experience limited symptoms at diagnosis, especially in hypothyroidism. We hypothesize that health-related quality of life (HR-QOL) is more severely impaired in subjects with more abnormal thyroid hormone function tests. This is a cross-sectional study of Dutch adults participating in the LifeLines Cohort Study between December 2009 and August 2010. In 9491 Western European participants (median age 45 years; 3993 men and 5498 women), without current or former use of thyroid medication, we compared HR-QOL using the RAND 36-Item Health Survey between subjects with normal thyrotropin (TSH) values and subjects with disturbed thyroid hormone status (serum TSH, free thyroxine, and free triiodothyronine). The influence of possible confounders (age, smoking, co-morbidity) on HR-QOL was evaluated as well. Suppressed TSH values (TSH < 0.5 mU/L) were found in 114 (1.2%), while 8334 (88.8%) had TSH within the normal range, 973 participants (10.3%) had TSH between 4 and 10 mU/L, and 70 (0.7%) had TSH > 10 mU/L. Men had a higher HR-QOL than women (70-92 vs. 65-89; p < 0.001), except for the domain "general health" (72 vs. 72; p = 0.692). Men with suppressed or elevated TSH values did not score significantly lower than euthyroid men for any of nine domains of the RAND 36-Item Health Survey. Compared with euthyroid women, women with suppressed TSH scored significantly lower in the domains "physical functioning" (84 vs. 89, p = 0.013) and "general health" (67 vs. 72, p = 0.036). Women with markedly elevated TSH (> 10 mU/L) had a score in all HR-QOL domains that was similar to that of women with normal TSH values. There were no differences in the physical component score and the mental component score between any of the TSH groups. Physical component score and mental component score were mainly determined by smoking status, co-morbidity, and body mass index or waist circumference. In this population-based study, HR-QOL scores of subjects with suppressed TSH values or markedly elevated TSH values were generally not significantly lower than those of subjects with normal or mildly elevated TSH values.

The Collateral Damage of Sodium Nitrates and Alleviating Properties of Vitamin C on Thyroid Gland of Adult Male Albino Rats: Toxicological, Histological and Ultrastructural study

Introduction: In the recent years, a considerable attention has been paid to the problem of nitrates due to their intensive use as agricultural fertilizers which reach to humans and animals by different routes. Purpose: To validate the toxic effects of nitrates in a short-term experiment (60 days) on thyroid gland and the possible ameliorative effect(s) of vitamin C. Materials and methods: Thirty two adult male albino rats were divided into four groups: group I (control) received distilled water, group II received 500mg∕kgvitamin C, group III received 130mg/kg sodium nitrates (NaNO3) and group IV received 130mg/kg NaNO3 plus 500mg∕kgvitamin C.All supplementations were taken as oral single dose daily for 60 days.At the end of experiment, blood samples were subjected to hormonal assay (T3, T4 and TSH serum levels). Also, thyroid glands' specimens were prepared for the optical and electron microscopic examination. Results: I- The biochemical analyses showed a significant decrease in serum T3 and T4 and a significant increase in TSH. II-Light microscopic examination of nitrates treated group revealed disturbed thyroid architecture in the form of heterogeneous poorly developed follicles. Enlarged deformed follicles with scanty vacuolated colloid, degenerative empty follicles and some fused follicles with exfoliated cells filled their lumen were observed. III-Electron microscopic examination showed stratification of follicular epithelial cells. Most of the follicular cells appeared with irregular nuclei, dilation of rER, many vacuoles and an apparent number of lysosomes. Also hypertrophy and hyperplasia of parafollicular-C cells were observed. An improvement of thyroid gland’s structure, ultrastructure and function was observed in vitamin C added group. In conclusion: This study concluded that nitrate is a thyroid gland disruptor via a mutual interdependence between the follicular, parafollicular and intra-thyroidal mast cells. The supplementation of vitamin C showed beneficial effects upon biochemical and patho-morphological alterations, developed in thyroid gland following exposure to toxic doses of nitrates. So, the recommendations are limitation of sodium nitrates uses, encourage dietary intake of vitamin C and routine analysis of thyroid function in the most nitrates' contaminated areas.

Letter to the Editor Amiodarone-induced thyrotoxicosis with paroxysmal supraventricular (ectopic atrial) tachycardia: and review of the literature

Letter to the Editor Amiodarone-induced thyrotoxicosis with paroxysmal supraventricular (ectopic atrial) tachycardia: and review of the literature

Thyroid disturbance related to chronic hepatitis C infection: role of CXCL10

Association between autoimmune thyroid diseases (AITD) and hepatitis C is controversial, but may occur or worsen during alpha-interferon treatment. The mechanism responsible for autoimmune diseases in infected patients has not been fully elucidated. This study aims to evaluate the frequency of AITD in chronic hepatitis C and the association of chemokine (CXC motif) ligand 10 (CXCL10) and AITD. One hundred and three patients with chronic hepatitis C and 96 controls were prospectively selected to clinical, hormonal, thyroid autoimmunity and ultrasound exams, besides thyroxine-binding globulin (TBG) and CXCL10 measurements and hepatic biopsies. The frequency of AITD among infected subjects was similar to controls. TT3 and TT4 distributions were right shifted, as was TBG, which correlated to both of them. Thyroid heterogeneity and hypoechogenicity were associated with AITD. Increased vascularization was more prevalent in chronic hepatitis C.CXCL10 was higher in infected patients (p=0.007) but was not related to thyroid dysfunction. Increase in CXCL10 levels were consistent with hepatic necroinflammatory activity (p=0.011). In summary, no association was found between chronic hepatitis C and AITD. Infected subjects had higher TT3 and TT4 which were correlated to TBG. Increased CXCL10 was not associated to thyroid dysfunction in HCV-infected population.

Communication Between the Calcium and cAMP Pathways Regulate the Expression of the TSH Receptor: TRPC2 in the Center of Action

Transient receptor potential (TRP) cation channels are widely expressed and function in many physiologically important processes. Perturbations in the expression or mutations of the channels have implications for diseases. Many thyroid disorders, as excessive growth or disturbed thyroid hormone production, can be a result of dysregulated TSH signaling. In the present study, we found that of TRP canonicals (TRPCs), only TRPC2 was expressed in Fischer rat thyroid low-serum 5% cells (FRTL-5 cells). To investigate the physiological importance of the channel, we developed stable TRPC2 knockdown cells using short hairpin RNA (shTRPC2 cells). In these cells, the ATP-evoked entry of calcium was significantly decreased. This led to increased cAMP production, because inhibitory signals from calcium to adenylate cyclase 5/6 were decreased. Enhanced cAMP signaling projected to Ras-related protein 1-MAPK kinase 1 (MAPK/ERK kinase 1) pathway leading to phosphorylation of ERK1/2. The activated ERK1/2 pathway increased the expression of the TSH receptor. In contrast, secretion of thyroglobulin was decreased in shTRPC2 cells, due to improper folding and glycosylation of the protein. We show here a novel role for TRPC2 in regulating thyroid cell function.

Improving the Concept of Recovery in Endocrine Disease by Consideration of Psychosocial Issues

Stringent criteria have been established to define remission by hormone parameters in several endocrine disorders. An example is provided by the criteria for cure of acromegaly (1). However, it is clear that such criteria are far from being comprehensive of a patient status, and often there is a need for filling a gap between the “hard data” of laboratory results and imaging findings on one hand, and the “soft information” related to the patient presentation and complaints on the other hand. Indeed, long-standing endocrine disorders may imply a degree of irreversibility of the pathological process and induce highly individualized affective responses based on each patient’s psychological assets and liabilities. In recent years, there has been increasing awareness of the unsatisfactory degree of remission that current therapeutic strategies entail in a variety of endocrine disorders. Studies concerned with psychological well-being, functional capacity, and social and interpersonal components of illness have provided new insights in clinical endocrinology (2–4). Psychiatric disturbances and impaired quality of life, which were present in the acute phase of illness, are often found to improve upon normalization of hormonal parameters (2, 3). However, disappearance of psychiatric symptoms and amelioration of quality of life are not always the case. This has been observed in several studies concerned with patients with either pituitary disease (acromegaly, Cushing’s disease, hyperprolactinemia, nonfunctioning pituitary adenomas, hypopituitarism, and GH deficiency) or nonpituitary endocrine disorders (thyroid disturbances, primary hyperparathyroidism, primary aldosteronism, adrenocortical insufficiency, and polycystic ovary syndrome) (2). There may be different reasons for a delayed or impaired process of recovery. Hormonal alterations are frequently associated with affective disturbances, which do not always remit upon normalization of blood parameters. Hormone replacement may not fully restore optimal endocrine balance, and subtle dysfunctions may still exert their influence on psychological states. This has been observed particularly in hypopituitarism ensuing from the treatment of pituitary disease (2–4). When surgery is performed (e.g. pituitary microadenomectomy in Cushing’s disease), the patient is likely to have expectations of a quick recovery toward his/her former normal condition. Unrealistic hopes of “cure” may foster discouragement and apathy. Harvey Cushing himself had acknowledged the difficult recovery of patients suffering from pituitary disease: “It is even more common for a physician or surgeon to eradicate or otherwise treat the obvious focus of disease, with more or less success, and to leave the mushroom of psychic deviations to vex and confuse the patient for long afterwards, if not actually to imbalance him” (5). Currently, however, the average endocrinologist is still unfamiliar with the psychosocial aspects of patient care, both in terms of personal skills and organizational structure, and lacks an adequate background for facilitating the process of recovery. The customary taxonomy does not include patterns of symptoms, severity of illness, effects of comorbid conditions, timing of phenomena, rate of progression of illness, functional capacity, and other clinical features that demarcate major prognostic and therapeutic differences among patients who otherwise seem deceptively similar because they have the same diagnosis and

Study of thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in subjects with dental fluorosis

Apart from its well-known deleterious dental and skeletal effects, fluoride excess can have toxic effects on many other tissues. Fluoride, when in excess, is known to interfere with thyroid gland function. Fluoride-induced thyroid disturbances similar to those observed in iodine deficiency state in spite of adequate iodine intake have been documented. Similar thyroid disturbances in individuals with dental fluorosis have not been well studied in populations with endemic fluorosis. This work was undertaken to study the effects of fluoride-induced thyroid disturbances in individuals with dental fluorosis. The study group included 65 subjects with dental fluorosis from endemic fluorosis populations. An additional control group was comprised of 10 subjects without dental fluorosis. The drinking water fluoride levels of the study populations were analyzed. Serum free FT3, FT4, and TSH levels of both groups were assessed. All subjects with dental fluorosis had serum levels of thyroid hormones (FT3, FT4, and TSH) within the normal range, with the exception of 1 individual, who had elevated levels of TSH. Statistical significance was found when FT3 and TSH values were compared with different Dean's index groups by a 1-way ANOVA test: FT3 (F = 3.4572; P=.0377) and TSH (F = 3.2649 and P=.0449). Findings of this study did not show any significant alterations in the levels of the thyroid hormones FT3, FT4, and TSH in subjects with dental fluorosis. Our observations suggest that thyroid hormone levels were not altered in subjects with dental fluorosis. Hence, future studies of this kind, along with more detailed investigations are needed.

125 Campath-1H for multiple sclerosis: a pain in the neck?

IntroductionAlemtuzumab (Campath-1H), the first humanised monoclonal antibody, is emerging as the most effective disease modifying treatment for multiple sclerosis (MS). One common side effect is thyroid gland disturbance. However, despite...

Recurrent pregnancy loss in patients with thyroid dysfunction

Purpose of the Review:Thyroid disturbances are common in women during their reproductive years. Thyroid dysfunction interferes with human reproductive physiology, reduces the likelihood of pregnancy and adversely affects pregnancy outcome, thus becoming relevant in the algorithm of reproductive dysfunction. This review highlights the gap in knowledge regarding the contribution of thyroid dysfunction in reproduction.Literature Reviewed:Following implantation, the maintenance of the pregnancy is dependent on a multitude of endocrinological events that will eventually aid in the successful growth and development of the fetus. It is estimated that approximately 8-12% of all pregnancy losses are the result of endocrine factors. Autoimmune thyroid disease is present in around 4% of young females and up to 15% are at risk because they are thyroid antibody-positive. There is a strong relationship between thyroid immunity on one hand and infertility, miscarriage, and thyroid disturbances in pregnancy and postpartum, on the other hand. Even minimal hypothyroidism can increase rates of miscarriage and fetal death and may also have adverse effects on later cognitive development of the offspring. Hyperthyroidism during pregnancy may also have adverse consequences.Summary:Pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality, and miscarriage. Universal screening for thyroid hormone abnormalities is not routinely recommended at present, but thyroid function must be examined in female with fetal loss or menstrual disturbances. Practitioners providing health care for women should be alert to thyroid disorders as an underlying etiology for recurrent pregnancy loss.

No thyroid abnormalities in patients submitted to cardiac catheterization in the first eighteen months of life.

No data are available about the risk of thyroid disturbance after exposure to low-dose radiation due to the use of cardiac catheterization in the first years of life. To determine the risk of functional and morphological thyroid abnormalities in a homogeneous cohort of patients who underwent diagnostic low-dose radiation for heart catheterization during the first 18 months of life. Fifty-five patients, submitted to cardiac catheterization during the first 18 months of life, underwent evaluation of the thyroid function and structure after a median period of 13 yr since the first radiation exposure. Sixty-eight unexposed controls matched for age and sex, underwent the same protocol. Twenty-two patients were then re-evaluated after a median period of 22 yr. Thyroid function resulted normal in both patients and controls. The prevalence of small thyroid nodules and inhomogeneous structures in ultrasound study was not augmented in irradiated patients compared to controls. No thyroid tumors or reduced thyroid volume were observed. Neither functional nor morphological disorders of the thyroid gland were demonstrated after a period up to 24 yr in patients exposed to diagnostic ionizing radiation for cardiac catheterization during the first 18 months of life.

Thyroid hormonal disturbances related to treatment of hepatitis C with interferon-alpha and ribavirin

OBJECTIVE:To characterize thyroid disturbances induced by interferon-alpha and ribavirin therapy in patients with chronic hepatitis C.INTRODUCTION:Interferon-alpha is used to treat chronic hepatitis C infections. This compound commonly induces both autoimmune and non-autoimmune thyroiditis.METHODS:We prospectively selected 26 patients with chronic hepatitis C infections. Clinical examinations, hormonal evaluations, and color-flow Doppler ultrasonography of the thyroid were performed before and during antiviral therapy.RESULTS:Of the patients in our study, 54% had no thyroid disorders associated with the interferon-alpha therapy but showed reduced levels of total T3 along with a decrease in serum alanine aminotransferase. Total T4 levels were also reduced at 3 and 12 months, but free T4 and thyroid stimulating hormone (TSH) levels remained stable. A total of 19% of the subjects had autoimmune interferon-induced thyroiditis, which is characterized by an emerge of antithyroid antibodies or overt hypothyroidism. Additionally, 16% had non-autoimmune thyroiditis, which presents as destructive thyroiditis or subclinical hypothyroidism, and 11% remained in a state of euthyroidism despite the prior existence of antithyroidal antibodies. Thyrotoxicosis with destructive thyroiditis was diagnosed within three months of therapy, and ultrasonography of these patients revealed thyroid shrinkage and discordant change in the vascular patterns.DISCUSSION:Decreases in the total T3 and total T4 levels may be related to improvements in the hepatocellular lesions or inflammatory changes similar to those associated with nonthyroidal illnesses. The immune mechanisms and direct effects of interferon-alpha can be associated with thyroiditis.CONCLUSION:Interferon-alpha and ribavirin induce autoimmune and non-autoimmune thyroiditis and hormonal changes (such as decreased total T3 and total T4 levels), which occur despite stable free T4 and TSH levels. A thyroid hormonal evaluation, including the analysis of the free T4, TSH, and antithyroid antibody levels, should be mandatory before therapy, and an early re-evaluation within three months of treatment is necessary as an appropriate follow-up.

A child with a deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects of thyroid hormone treatment

The monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T(3)) uptake. Mutations of this transporter determine a distinct X-linked psychomotor retardation syndrome (Allan-Herndon-Dudley syndrome (AHDS)) that is attributed to disturbed thyroid hormone levels, especially elevated T(3) levels. We describe the genetic analysis of the MCT8 gene in a patient suspected for AHDS and the clinical and endocrine effects of L-thyroxine (LT(4)) or liothyronine (LT(3)) treatment intending to overcome the T(3) uptake resistance through alternative transporters. The six exons of the MCT8 gene were amplified individually by PCR. As multiple exons were missing, the length of the X-chromosomal deletion was determined by a dense SNP array, followed by PCR-based fine mapping to define the exact borders of the deleted segment. The clinical and endocrine data of the patient during 6.5 years of LT(4) treatment and two periods (3 months each) of low- and high-dose LT(3) were evaluated. A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T(3) at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient. We identified a 70 kb deletion encompassing exons 2-6 of the MCT8 gene in our AHDS patient. Both LT(4) and LT(3) administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.

Thyroid function in the nutritionally obese child and adolescent

In recent years, there has been an increasing focus on thyroid function in obese children. There is controversy concerning whether the changes in the levels of thyroid hormones and thyroid-stimulating hormone (thyrotropin - TSH) in obesity are causes or consequences of weight status and whether these subtle differences merit treatment with thyroxine. This review aimed to study the prevalence of disturbed thyroid hormone and TSH values in childhood obesity and the underlying pathophysiologic mechanisms linking obesity to thyroid function. In the past 18 months, four studies demonstrated moderate elevation of TSH concentrations in 10-23% of obese children, which was associated with normal or slightly elevated thyroxine and triiodothyronine values. Two studies reported ultrasonographic hypoechogenicity of the thyroid in obese children with hyperthyrotropinemia, which was not caused by autoimmune thyroiditis; therefore, the authors hypothesized a link to chronic inflammation in obesity. Weight loss led to a normalization of elevated TSH levels in two studies. The adipokine leptin is the most promising link between obesity and hyperthyrotropinemia since leptin stimulates the hypothalamic-pituitary-thyroid. The elevated TSH levels in obesity seem a consequence rather than a cause of obesity. Therefore, treatment of hyperthyrotropinemia with thyroxine seems unnecessary in obese children.

What is hot in experimental thyroidology?

Over the recent years, considerable progress has been made in elucidating processes that are critical for thyroid hormone (TH) synthesis and action. In this issue of Thyroid Research several German groups dedicated to thyroid research have assembled and discussed novel aspects of thyroid hormone action with the perspective to improve diagnosis and therapy of thyroid disorders by better understanding disturbed thyroid differentiation. The over-arching theme addressed in the contributions of this special issue relates to the main focus of current thyroid research and treatment of thyroid disesase, i.e. “What defines thyroid health?” [1]. Thereby the putative role of seemingly established players in TH synthesis and action are revisited. A report on a patient characterized by a novel germline TSH-receptor mutation links this case of non-autoimmune hyperthyroidism to new impliations in TSH-receptor structure [2]. The study highlights the importance of introducing novel diagnostic approaches to the clinics, because this particular mutation in the TSH-receptor is correlated to altered Gq-signalling pathways, thereby pointing to an important role of Gq signalling in the thyroid It is known only since recently that transport of TH is an active and regulated mechanism. The monocarboxylate transporter 8 (MCT8) is a crucially important transporter of TH and it transports triiodothyronine (T3) specifically well. Mutations in MCT8 are known to cause a severe syndrome of X-linked mental retardation known as Allan-Herndon Dudley syndrome. Based on homology modeling all of the currently reported pathogenic mutations in MCT8 are studied in the article by Kleinau et al. [3]. A focus is set on identification of those MCT8 mutations that are most sensitive for substrate transport with the goal to simulate in silico the potencies of future therapies based on TH transporter-specific inhibitors mimicking TH structurally. Besides MCT8 other transporters have been proposed to play important roles in TH transport (MCT10, OATP1C1, OATP1A2, OATP14, LAT1 and LAT2). The structure-function relationships of primary TH transporters like MCT8 and additional, so-called secondary TH transporters such as those listed above is reviewed by Kinne et al. [4] with special attention on their expression profiles, transport specificities and substrates. Similarities and differences in structure and molecular features of the known and suspected TH transporters are compared between man and mouse, in particular asking their crucial impact on TH actions in the central nervous system. TH actions in the brain and clinical consequences of non-classical, rather novel treatment protocols to relieve symptoms of severe mood and depression disorders is reviewed in the article by Pilhatsch et al. [5]. For a long time, only genomic actions of TH, namely of T3 were recognized by both, thyroid researchers and clinicians. However this picture has to be revised as non-classical, non-genomic TH actions were described which lead to activation of alternative signaling pathways via PI3K and MAPK. The impact and perspectives of these recent findings are summarized by Moller and Brocker-Preus [6] who comment on the outcomes of activation of alternative signaling pathways on transcriptional regulation of TH target cells. Non-classical and classical TH actions must be taken into consideration for better management of thyroid malignancies. Moreover, it is increasingly appreciated that disturbances in TH synthesis occur in thyroid tumorigenesis and that disturbed TH action affects carcinogenesis in general. Of the many novel aspects in thyroid carcinogenesis, it was the recent identification of miRNAs and their intricate involvement in the regulation of transcriptional, translational and epigentic control mechanisms that provides one of the most promising diagnostic and high-potential, future therapeutic tool. The aspects of miRNA relevance for thyroid pathologies are discussed by Braun and Huttelmaier [7]. Likewise, regulation of transcription and translation by RNA binding proteins is addressed in the article by Trojanowicz et al. The adenylate uridylate-rich element binding proteins AUF together with HuR was reported to regulate mRNA stability and could hence participate in thyroid carcinogenesis. RNA binding proteins may harbor multifunctional properties that not only affect thyrocyte differentiation but could also affect TH synthesis [8]. Finally, the characterization of protein transport pathways and the identification of altered trafficking in thyroid carcinoma cells are approached in the experimental study by Tedelind et al. [9] that investigated the cathepsins which are known as thyroglobulin-processing enzymes with important functions in TH biosynthesis. We believe that the papers collected for this special issue of Thyroid Research will have a stimulatory effect not only for thyroid researchers but will be interesting for those from associated disciplines.