[Monitoring of treatment in thyroid diseases]

The effectiveness of antithyroid drug treatment of Graves' hyperthyroidism is documented by measuring initially free T4 and free T3 and later free T4, free T3 and TSH. An elevated titer of the Graves'-specific thyroid stimulating antibodies is not usually rechecked before the end of the antithyroid drug therapy. Thyroxine treatment of primary hypothyroidism is controlled by TSH measurements. In patients in whom TSH levels might be affected by drugs or nonthyroid diseases, free T4 is measured in addition to TSH. The assessment of the treatment of Hashimoto's chronic thyroiditis consists of the control of the therapy of its associated hypothyroidism. In subacute thyroiditis de Quervain control of the effectiveness of the analgesic therapy is most important. To check the effect of thyroid hormone treatment given with the intent to reduce goiter size, serial sonographies are of great value. In the follow-up of patients with thyroid carcinomas, measurements of thyroglobulin (for papillary and follicular thyroid cancers) and of calcitonin (for medullary thyroid cancers) in the serum as well as thyroid scans and other imaging procedures play an important role.

Thyroid function and serum electrolytes: does an association really exist?

Thyroid hormone is a central regulator of body functions. Disorders of thyroid function are considered to be a cause of electrolyte disorders. Only few data on the association between thyroid function and electrolyte disorders exists.

[ABC of thyroid diseases and their treatment]

Thyroid diseases are caused by a disturbance of thyroid hormone secretion, inflammations or tumors of the thyroid or combinations thereof. Most important causes for hyperthyroidism are Graves' disease and toxic nodular goiters (including toxic adenomas). Hypothyroidism is often caused by Hashimoto's chronic thyroiditis and can occur in patients after thyroidectomy. Chronic hashimoto's thyroiditis and subacute de Quervain's thyroiditis are the thyroid inflammations most frequently seen. Graves' disease and Hashimoto's thyroiditis are autoimmune thyroid diseases. Thyroid tumors encompass benign solitary nodules, diffuse and nodular goiters, papillary, follicular, medullary and anaplastic carcinomas.

Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies

The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels ≥10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial).

Subclinical thyroid dysfunction and cognitive decline in old age

BACKGROUND Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). METHODS Prospective longitudinal study of men and women aged 70-82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests. RESULTS Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up. CONCLUSION We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.

Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions

The vertebrate thyroid system is important for multiple developmental processes, including eye development. Thus, its environmentally induced disruption may impact important fitness-related parameters like visual capacities and behaviour. The present study investigated the relation between molecular effects of thyroid disruption and morphological and physiological changes of eye development in zebrafish (Danio rerio). Two test compounds representing different molecular modes of thyroid disruption were used: propylthiouracil (PTU), which is an enzyme-inhibitor of thyroid hormone synthesis, and tetrabromobisphenol A (TBBPA), which interacts with the thyroid hormone receptors. Both chemicals significantly altered transcript levels of thyroid system-related genes (TRα, TRβ, TPO, TSH, DIO1, DIO2 and DIO3) in a compound-specific way. Despite these different molecular response patterns, both treatments resulted in similar pathological alterations of the eyes such as reduced size, RPE cell diameter and pigmentation, which were concentration-dependent. The morphological changes translated into impaired visual performance of the larvae: the optokinetic response was significantly and concentration-dependently decreased in both treatments, together with a significant increase of light preference of PTU-treated larvae. In addition, swimming activity was impacted. This study provides first evidence that different modes of molecular action of the thyroid disruptors can be associated with uniform apical responses. Furthermore, this study is the first to show that pathological eye development, as it can be induced by exposure to thyroid disruptors, indeed translates into impaired visual capacities of zebrafish early life stages.

[Inherited alopecia X in Pomeranians]

Four male Pomeranians that showed alopecia with an age of onset between five months and eight years were investigated.The aim of the investigation was to clarify whether the affected dogs had alopecia X and whether their symptoms might be due to a hereditary defect.The four affected dogs showed hairless patches at the root of the tail, at the back, at the limbs from the thigh to the tarsus and at the abdomen. Within the hairless patches some islets with sparse hair were present. In hairless patches the skin was dark pigmented. Besides the alopecia and hyperpigmentation no other symptoms were found according to anamnestic and clinical examination. History, clinical examinations, laboratory diagnostics, and histopathology of skin biopsies allowed the diagnosis of alopecia X in three affected male dogs.The last one of the affected dogs additionally had slightly reduced thyroid hormone levels. Based on identical symptoms and the close relatedness of all four animals, it was assumed that the fourth affected dog also had alopecia X.The available data possibly indicate a monogenic autosomal dominant inheritance, however a recessive inheritance can not be excluded at this time.

Analysis of left ventricular function of the mouse heart during experimentally induced hyperthyroidism and recovery

Many of the clinical manifestations of hyperthyroidism are due to the ability of thyroid hormones to alter myocardial contractility and cardiovascular hemodynamics, leading to cardiovascular impairment. In contrast, recent studies highlight also the potential beneficial effects of thyroid hormone administration for clinical or preclinical treatment of different diseases such as atherosclerosis, obesity and diabetes or as a new therapeutic approach in demyelinating disorders. In these contexts and in the view of developing thyroid hormone-based therapeutic strategies, it is, however, important to analyze undesirable secondary effects on the heart. Animal models of experimentally induced hyperthyroidism therefore represent important tools for investigating and monitoring changes of cardiac function. In our present study we use high-field cardiac MRI to monitor and follow-up longitudinally the effects of prolonged thyroid hormone (triiodothyronine) administration focusing on murine left ventricular function. Using a 9.4 T small horizontal bore animal scanner, cinematographic MRI was used to analyze changes in ejection fraction, wall thickening, systolic index and fractional shortening. Cardiac MRI investigations were performed after sustained cycles of triiodothyronine administration and treatment arrest in adolescent (8 week old) and adult (24 week old) female C57Bl/6 N mice. Triiodothyronine supplementation of 3 weeks led to an impairment of cardiac performance with a decline in ejection fraction, wall thickening, systolic index and fractional shortening in both age groups but with a higher extent in the group of adolescent mice. However, after a hormonal treatment cessation of 3 weeks, only young mice are able to partly restore cardiac performance in contrast to adult mice lacking this recovery potential and therefore indicating a presence of chronically developed heart pathology.

Growth hormone regulates growth hormone receptor gene transcription in primary human thyroid cells

In this study the regulation of GH-receptor gene (GHR/GHBP) transcription by different concentrations of GH (0, 12.5, 25, 50, 150, 500 ng/ml) with and without variable TSH concentrations (0.5, 2, 20 mU/l) in primary human thyroid cells cultured in serum-free hormonally-defined medium was studied. The incubation time was 6 h and GHR/GHBP mRNA expression was quantitatively assessed by using PCR amplification at hourly intervals. Correlating with the GH-concentrations added a constant and significant increase of GHR/GHBP gene transcription was found. After the addition of 12.5 ng/ml GH, GHR/GHBP mRNA concentration remained constant over the incubation period of 6 h but in comparison with the experiments where no GH was added there was a significant change of GHR/GHBP mRNA expression. Following the addition of 25 ng/ml GH a slight but further increase of GHR/GHBP transcription products was seen which increased even more in the experiments where higher GH concentrations were used. These data focusing on GHR/GHBP gene transcription derived from cDNA synthesis and quantitative PCR amplification were confirmed by run-on experiments. Furthermore, cycloheximide did not affect these changes supporting the notion that GH stimulates GHR/GHBP gene transcription directly. In a second set of experiments, in combination with variable TSH levels, identical GH concentrations were used and no difference in either GHR/GHBP mRNA levels or in transcription rate (run-on experiments) could be found. In conclusion, we report data showing that primary thyroid cells express functional GH-receptors in which GH has a direct and dose dependent effect on the GHR/GHBP gene transcription. Furthermore, TSH does not a have a major impact on GHR/GHBP gene regulation.

[Goiter and nodular thyroid disease: clinical guidelines for diagnosis and treatment. (Waiting? Hormone therapy? Surgery? radioiodine?)]

Nodular thyroid disease is a common problem. We present clinical guidelines for the management of patients with thyroid nodules, multinodular goiters and thyroid cysts for use by primary physicians. In the initial evaluation ultrasonography of the thyroid and fine-needle aspiration biopsy (FNAB) is recommended. FNAB has become the cornerstone in the evaluation of solitary thyroid nodules, cysts and dominant nodules within multinodular goiters. If the procedure is done properly, it should have a false-negative rate of less than 5% and a false-positive rate of not more than 1%. Thyroid radionuclide scans are less frequently used in the initial evaluation of a nodular goiter. Surgery is the primary therapy for patients with nodular thyroid disease. Other available treatment options are radioiodine and TSH-suppression with thyroxine. The main indications for surgery in euthyroid patients with thyroid nodule or with nontoxic multinodular goiter are recently documented or suspected malignancy, compression of the trachea and esophagus, significant growth of the nodule, recurrence of a cyst after aspiration, neck discomfort and cosmetic concern.

Nuclear cysteine cathepsin variants in thyroid carcinoma cells

The cysteine peptidase cathepsin B is important in thyroid physiology by being involved in thyroid prohormone processing initiated in the follicular lumen and completed in endo-lysosomal compartments. However, cathepsin B has also been localized to the extrafollicular space and is therefore suggested to promote invasiveness and metastasis in thyroid carcinomas through, e.g., ECM degradation. In this study, immunofluorescence and biochemical data from subcellular fractionation revealed that cathepsin B, in its single- and two-chain forms, is localized to endo-lysosomes in the papillary thyroid carcinoma cell line KTC-1 and in the anaplastic thyroid carcinoma cell lines HTh7 and HTh74. This distribution is not affected by thyroid stimulating hormone (TSH) incubation of HTh74, the only cell line that expresses a functional TSH-receptor. Immunofluorescence data disclosed an additional nuclear localization of cathepsin B immunoreactivity. This was supported by biochemical data showing a proteolytically active variant slightly smaller than the cathepsin B proform in nuclear fractions. We also demonstrate that immunoreactions specific for cathepsin V, but not cathepsin L, are localized to the nucleus in HTh74 in peri-nucleolar patterns. As deduced from co-localization studies and in vitro degradation assays, we suggest that nuclear variants of cathepsins are involved in the development of thyroid malignancies through modification of DNA-associated proteins.

Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts

American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events.

Inhibition of iodine organification and regulation of follicular size in rat thyroid tissue in vitro

The factors mediating the accumulation of thyroglobulin are of great importance to the understanding of the pathogenesis of human and experimentally induced colloid goiters. To elucidate further the underlying cellular mechanism, thyroid fragments from newborn rats were incorporated into semisolid alginate beads and were cultured as three-dimensional organoids for up to 21 d. In five parallel cultures, the medium contained either no supplements (group A), Nal (group B), thyroid-stimulating hormone (TSH) (group C), Nal plus TSH in the same concentrations as B and C (group D), or Nal and TSH (as in group D) plus methimazole (MMI, group E). The thyroid organoids maintained morphological integrity, functional activity, and ability to proliferate in vitro. Addition of iodine to the cultures significantly increased mean (+/-SEM) follicular diameters from 19.5 +/- 0.7 microm in controls to 33.9 +/- 2.2 microm (p < 0.0001) when NaI was added alone (group B), and 30.4 +/- 1.7 microm (p < 0.0001) when combined with TSH (group D). The effect of NaI on follicular size was abolished by MMI (group E, follicular diameter 23.5 +/- 1.3 microm). The results presented support the recent finding, using a rat colloid goiter model, that not only TSH but also iodine organification or its inhibition are important factors in modulating follicular morphology.

An unusual case of galactorrhea in a postmenopausal woman complicating breast reduction

Galactorrhea is a relatively common condition, but has rarely been seen following breast reduction surgery. To date there are only seven cases reported in the literature, all in premenopausal women. Postsurgical galactorrhea is a diagnosis of exclusion and differential diagnosis is extensive. Common causes should be excluded first. We present the case of a 56-year-old postmenopausal woman who underwent bilateral breast reduction and developed galactorrhea 2 months postoperatively. MRI scan of the skull as well as Thyroid-Stimulating Hormone (TSH), prolactin levels were normal. She was on long-term hormonal replacement therapy. Because of suspected nerve-related pain in her right breast she was commenced on amitriptyline. We hypothesise that galactorrhea may have been caused by underlying neuroma or irritation of the anterior branch of the T4 intercostal nerve or hormonal replacement therapy or a combination of both.

Subclinical thyroid dysfunction and fracture risk: a meta-analysis.

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.