Adult idiopathic myxedema (IM) is believed to be the end stage of a lymphocytic thyroiditis in which humoural and cellular autoimmune processes lead to failure of the thyroid function (Strakosh et al. 1982; Pinchera et al. 1985). Recent data indicate that this disease may be associated with the presence of autoantibodies which block the effect of TSH on thyroid adenylate cyclase (Matsuura et al. 1980; Konishi et al. 1983; Arikawa et al. 1985) and cell growth (Drexhage et al. 1981). These TSH blocking autoantibodies (TBkAb) could play a role in the pathogenesis of hypothyroidism. Human thyroid cells in primary culture (Konishi et al. 1983), human thyroid plasma membrane (Matsuura et al. 1980; Arikawa et al. 1985) or slices (Drexhage et al. 1981; Steeln et al. 1984) have been used to measure TBkAb. In the present report we describe a new method for the detection of TBkAb by determining their blocking
P. Vitti, L. Chiovato, A. Lombardi, G. Lopez, C. Mammoli, F. Santini, G. F. Fenzi, and A. Pinchera
F Santini, A Pinchera, G Ceccarini, M Castagna, V Rosellini, C Mammoli, L Montanelli, V Zucchi, IJ Chopra, and L Chiovato
OBJECTIVE: Thyroid hormone is essential for maintaining normal neurological functions both during development and in adult life. Type III-iodothyronine deiodinase (D3) degrades thyroid hormones by converting thyroxine and 3,5,3'-triiodothyroinine (T3) to inactive metabolites. A regional expression of D3 activity has been observed in the human central nervous system (CNS), and a critical role for D3 has been suggested in the regulation of local T3 content in concert with other enzymes. DESIGN: This study was undertaken to further characterize D3 activity in human CNS and to understand its role in the local regulation of T3 content. METHODS: Autoptic specimens from various areas of human CNS were obtained 6--27 h postmortem from 14 donors who died from cardiovascular accident, neoplastic disease or infectious disease. D3 was determined by measuring the conversion of T3 to 3,3'-diiodothyronine. The T3 content was measured by radioimmunoassay in ethanol extracts, using a specific antiserum. RESULTS: High levels of D3 activity were observed in hippocampus and temporal cortex, lower levels being found in the thalamus, hypothalamus, midbrain cerebellum, parietal and frontal cortex, and brain stem. An inverse relationship between D3 activity and T3 content in these areas was demonstrated. CONCLUSIONS: We have concluded that D3 contributes to the local regulation of T3 content in the human CNS.
M Tonacchera, P Agretti, G Ceccarini, R Lenza, S Refetoff, F Santini, A Pinchera, L Chiovato, and P Vitti
OBJECTIVE: The human sodium iodide symporter (hNIS) is a candidate autoantigen in autoimmune thyroid diseases. To investigate the possible existence of autoantibodies able to interfere with the biological activity of hNIS, an assay was developed using a cell line stably expressing hNIS. METHODS: hNIS complementary cDNA cloned in pcDNA3 and a neomycin resistance gene vector were co-transfected into CHO cells. After selection with geneticin, a cell line termed PA4, showing the highest level of Na(125)I uptake, was characterized. The time course of iodide uptake was evaluated by incubating PA(4) cells with 10 micromol/l NaI and 0.1 microCi Na(125)I for a period up to 90 min. The accumulation of iodide increased linearly between 2 and 10 min, reaching a plateau at 45 min. The curve of iodide efflux mirrored that of iodide influx. Both perchlorate and thiocyanate inhibited iodide uptake in PA(4) cells in a dose-dependent manner starting from concentrations as low as 0.01 and 0.1 micromol/l respectively and complete inhibition was obtained at concentrations of 100 micromol/l perchlorate and 1000 micromol/l thiocyanate. The sensitivity of the inhibition assay was further improved using both inhibitors after 5 min incubation and in the absence of cold NaI. RESULTS: Included in the study were 42 patients with Graves' disease (25 had active hyperthyroidism, ten were euthyroid and seven had hypothyroidism); 34 patients with Hashimoto's thyroiditis (one was euthyroid, four had subclinical hypothyroidism and 29 were overtly hypothyroid); and 19 with atrophic thyroiditis (all hypothyroid). Four out of eight whole sera from patients with Hashimoto's thyroiditis, and 8 out of 25 whole sera from patients with Graves' disease caused an inhibition of iodide uptake in PA(4) cells greater than 20% but also in 4 out of 15 sera from normal subjects. This inhibition activity exerted by sera from patients and controls was lost after dialyzing against buffer. Accordingly, IgGs purified from sera of all patients with Graves' disease and with Hashimoto's thyroiditis or atrophic thyroiditis were devoid of any effect on iodide uptake. CONCLUSIONS: In conclusion, we believe that autoantibodies able to block the function of hNIS are very rare.
T Rago, E Fiore, M Scutari, F Santini, G Di Coscio, R Romani, P Piaggi, C Ugolini, F Basolo, P Miccoli, A Pinchera, and P Vitti
To evaluate the risk of papillary thyroid carcinoma (PTC) at fine-needle aspiration (FNA) cytology in 34 120 patients.
False positive and false negative rates of FNA cytology were 1.2 and 1.8% in comparison with the histology in 3406 nodules from 3004 patients who underwent surgery. PTC (901 cases) was more frequent in solitary nodule (SN; 446/13 549, 3.3%) than in multinodular goiter (MNG; 411/19 923, 2%, χ 2=48.8; P<0.0001), and in males (209/6382, 3.3%) than in females (648/26 945, 2.40%, χ 2=15.58; P<0.0001). PTC prevalence in Graves' disease (GD; 13/286, 4.5%) and Hashimoto's thyroiditis (HT; 31/508, 6.1%) was higher than in SN, this difference being significant in HT (χ 2=8.7; P=0.003), but not in GD (χ 2=1.6; P=0.2).
Using the multiple logistic regression analysis, independent risk predictors of PTC were determined, which were younger age (odds ratio (OR)=0.97, confidence interval (CI) 0.964–0.974; P<0.0001), male gender (OR=1.44, CI 1.231–1.683; P<0.0001), and SN versus MNG (OR=0.63, CI 0.547–0.717; P<0.0001). The individual risk predictivity was highly improved by including serum TSH in the prediction model, which was measured at FNA in 11 919 patients.
A cytology suspicious or indicative of PTC was associated with younger age, male gender, and solitary versus multiple nodularity. These clinical parameters, together with serum TSH, may allow formulation of an algorithm that could be usefully applied to predict the risk of PTC in individual patients when cytology does not give a diagnostic result.
R Pasquali, F Casanueva, M Haluzik, L van Hulsteijn, S Ledoux, M P Monteiro, J Salvador, F Santini, H Toplak, and O M Dekkers
Obesity is an emerging condition, with a prevalence of ~20%. Although the simple measurement of BMI is likely a simplistic approach to obesity, BMI is easily calculated, and there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity. An increased BMI leads to a number of hormonal changes. Additionally, concomitant hormonal diseases can be present in obesity and have to be properly diagnosed – which in turn might be more difficult due to alterations caused by body fatness itself. The present European Society of Endocrinology Clinical Guideline on the Endocrine Work-up in Obesity acknowledges the increased prevalence of many endocrine conditions in obesity. It is recommended to test all patients with obesity for thyroid function, given the high prevalence of hypothyroidism in obesity. For hypercortisolism, male hypogonadism and female gonadal dysfunction, hormonal testing is only recommended if case of clinical suspicion of an underlying endocrine disorder. The guideline underlines that weight loss in obesity should be emphasized as key to restoration of hormonal imbalances and that treatment and that the effect of treating endocrine disorders on weight loss is only modest.
L T van Hulsteijn, R Pasquali, F Casanueva, M Haluzik, S Ledoux, M P Monteiro, J Salvador, F Santini, H Toplak, and O M Dekkers
The increasing prevalence of obesity is expected to promote the demand for endocrine testing. To facilitate evidence guided testing, we aimed to assess the prevalence of endocrine disorders in patients with obesity. The review was carried out as part of the Endocrine Work-up for the Obesity Guideline of the European Society of Endocrinology.
Systematic review and meta-analysis of the literature.
A search was performed in MEDLINE, EMBASE, Web of Science and COCHRANE Library for original articles assessing the prevalence of hypothyroidism, hypercortisolism, hypogonadism (males) or hyperandrogenism (females) in patients with obesity. Data were pooled in a random-effects logistic regression model and reported with 95% confidence intervals (95% CI).
Sixty-eight studies were included, concerning a total of 19.996 patients with obesity. The pooled prevalence of overt (newly diagnosed or already treated) and subclinical hypothyroidism was 14.0% (95% CI: 9.7–18.9) and 14.6% (95% CI: 9.2–20.9), respectively. Pooled prevalence of hypercortisolism was 0.9% (95% CI: 0.3–1.6). Pooled prevalence of hypogonadism when measuring total testosterone or free testosterone was 42.8% (95% CI: 37.6–48.0) and 32.7% (95% CI: 23.1–43.0), respectively. Heterogeneity was high for all analyses.
The prevalence of endocrine disorders in patients with obesity is considerable, although the underlying mechanisms are complex. Given the cross-sectional design of the studies included, no formal distinction between endocrine causes and consequences of obesity could be made.