Enrico Macchia

Environmental Iodine Intake and Thyroid Dysfunction During Chronic Amiodarone Therapy

Amiodarone, an iodine-containing drug used frequently in the treatment of cardiac arrhythmias and angina pectoris, has many effects on thyroid hormone metabolism, including decreasing the production of triiodothyronine (T3) and decreasing the clearance of thyroxine and reverse T3. These effects result in elevated serum thyroxine and reverse T3 concentrations and decreased serum T3 concentrations. In addition, iodine-induced hyperthyroidism or hypothyroidism may occur in patients chronically treated with amiodarone. This study is a retrospective analysis of the incidence of thyroid dysfunction in Lucca and Pisa, West Tuscany, Italy, and in Worcester, Massachusetts. Hyperthyroidism was a more frequent (9.6%) complication of amiodarone therapy in West Tuscany, where iodine intake is moderately low; hypothyroidism was more frequent (22%) in Worcester, where iodine intake is sufficient. In patients receiving chronic amiodarone therapy, clinically suspected hyperthyroidism is best confirmed by showing elevations in serum T3 or free T3 concentrations; hypothyroidism is best diagnosed by showing an elevated serum thyrotrophin concentration. Thyroid function should be carefully monitored in patients receiving amiodarone chronically, especially if they have goiter or Hashimotos thyroiditis.

Thyroid carcinoma in thyrotoxic patients treated by surgery

We report the incidence of thyroid cancer in a series of 1832 consecutive patients seen for thyrotoxicosis of any etiology during 1970 and 1985 in our department. Surgical treatment for thyrotox-icosis was selected as the treatment of choice in 179 patients (9.8%), 86 with toxic diffuse goiter (TDG), 21 with toxic nodular goiter (TNG) and 40 with toxic adenoma (TA). The presence of thyroid cancer was found in 11 patients for a total incidence of 6.1%. Six patients had TDG (percent incidence in this group 6.9%), 4 patients had TNG (7.5%) and 1 had TA (2.5%). While the presence of thyroid cancer was totally unsuspected in TNG and TA, in TDG 4 out of 6 patients found to have a cancer, had been suspected before surgery. When a thyroid nodule was present in a toxic diffuse goiter the possibility to face with a malignant lesion reached 22.2% of the cases (4 out of 18 cases), while only 2 out of 68 patients (2.9%) with TDG and no nodule had thyroid cancer. These results confirm recent other series reporting the frequent association of hyperthyroidism and thyroid cancer and suggest that in thyrotoxic patients any nodule must be screened carefully to rule out malignancy.

Androgen receptor polymorphism (CAG repeats) and androgenicity

Objective  Polymorphism of the androgen receptor (AR) has been related to various pathophysiological conditions, such as osteoporosis and infertility. The objectives of this study were to evaluate the frequency of distribution in a normal Italian population and to assess CAG repeats (CAGr) in other conditions, such as hypoandrogenism, potentially influenced by AR polymorphism.

RECIPROCAL CHANGES OF SERUM THYROGLOBULIN AND TSH IN RESIDENTS OF A MODERATE ENDEMIC GOITRE AREA

Subjects living in iodine deficient areas were reported to have elevated serum thyroglobulin (Tg) concentrations. This finding was interpreted as related to thyroid stimulation. Discrepant results, however, were found when serum Tg concentrations were correlated either with serum TSH or with goitre size. In this study we investigated the relationships between goitre size, serum Tg and serum TSH in 488 unselected adult subjects living in an endemic area of North‐Western Tuscany (Garfagnana district). The control group comprised 352 subjects residing in a non‐endemic area. In the endemic area a high prevalence of goitre was found (80·1%), thyroid enlargement being slight to moderate in the majority of cases and very large only in six subjects. Serum Tg concentrations increased and serum TSH levels decreased with the size of goitre. Statistical analysis by the chi‐square cross correlation test showed that the converse changes of serum Tg and serum TSH in relation to goitre size were highly significant. These findings indicate that the increase of serum Tg occurring in endemic goitrous subjects may be related to factors other than TSH stimulation. Functional autonomy of the thyroid may account for the finding of low serum TSH and elevated serum Tg values in patients with large goitres. The present data do not exclude the possibility that the release of Tg is influenced by TSH stimulation, but indicate that other factors may be responsible for the increased levels of Tg found in endemic goitre.

IS HUMORAL THYROID AUTOIMMUNITY RELEVANT IN AMIODARONE IODINE-INDUCED THYROTOXICOSTS (AIIT)?

Amiodarone, an iodine containing drug, may induce thyrotoxicosis by an uncertain mechanism. In this study the role of thyroid autoimmunity was evaluated in 28 consecutive patients referred to us because they had become hyperthyroid during long‐term amiodarone administration. Titres of thyroglobulin and thyroid microsomal antibodies, TSH binding‐inhibitory and thyroid stimulating antibodies were evaluated. Underlying thyroid disorders were demonstrated in 20 patients (9 of them had toxic diffuse goitre, seven toxic multinodular goitre and four toxic adenoma), while eight patients did not show any apparent thyroid gland abnormality. Circulating thyroid autoantibodies could be found in all amiodarone iodine‐induced hyperthyroid patients with toxic diffuse goitre and in one with toxic multinodular goitre, whilst they were absent in the other patients. These studies suggest that thyroid autoimmunity has little if any role in the development of thyrotoxicosis in amiodarone treated patients without underlying thyroid disorders. Furthermore, in amiodarone‐iodine‐induced thyrotoxicosis associated with various thyroid diseases, the humoral markers of thyroid autoimmunity show an incidence similar to that observed in spontaneous hyperthyroidism.

Thyroid Hormone Receptor (α) Distribution in Hamster and Sheep Brain: Colocalization in Gonadotropin-Releasing Hormone and Other Identified Neurons1

Thyroid hormones appear to play an important role in the seasonal reproductive transitions of a number of mammalian and avian species. These seasonal transitions as well as the effects of thyroid hormones on the reproductive neuroendocrine axis are mediated by the GnRH system. How thyroid hormones affect the GnRH system is unclear. Double label immunocytochemistry was used to examine GnRH- and other neurotransmitter/neuropeptide-containing neurons for thyroid hormone receptor (alphaTHR) colocalization in two seasonal breeders, the golden hamster and the sheep. AlphaTHR was identified in hamster and sheep brain by Western blot analysis. Furthermore, alphaTHR immunoreactivity was widely distributed in brain and was colocalized in identified populations: GnRH neurons (hamster, 28%; sheep, 46%); dopaminergic neurons of the A14 (hypothalamic) and A16 (olfactory bulb) cell groups, but not in the hypothalamic A13 cell group; and neurophysin-immunoreactive neurons of the supraoptic and paraventricular nuclei. The finding of alphaTHR in GnRH and A14 dopamine neurons provides an anatomical substrate for direct thyroid hormone action on the reproductive neuroendocrine system of these two seasonally breeding species. It remains to be determined whether the GnRH gene itself or the gene of another constituent within the same GnRH neuron is responsive to thyroid hormones.

Proportion of type 1 and type 2 amiodarone‐induced thyrotoxicosis has changed over a 27‐year period in Italy

Context  Two main forms of amiodarone‐induced thyrotoxicosis (AIT) exist. Type 1 AIT is a form of iodine‐induced hyperthyroidism. Its management is complex and includes thionamides, potassium perchlorate and, occasionally, thyroidectomy. Type 2 AIT is a destructive thyroiditis, responds to glucocorticoids, and usually does not require further thyroid treatment once euthyroidism has been restored.

Familial Dysalbuminemic Hyperthyroxinemia: A Persistent Diagnostic Challenge

Familial dysalbuminemic hyperthyroxinemia (FDH)1 is a well-characterized condition associated with increased circulating total thyroxine (T4) concentrations and normal physiological thyroid function. It is caused by mutations in the ALB (albumin) gene that increase the affinity of albumin for T4 by approximately 60-fold. When measured by a technique that minimally disturbs the equilibria between T4 and its serum binding proteins, such as equilibrium or symmetric dialysis (SyD) performed in a near-physiological medium, the free T4 (FT4) value is characteristically within the reference interval. Assays that rely on the competition of a T4 analog with unbound T4 in the sample can give spuriously high results in FDH patients, because albumin binding of the T4 analog is enhanced by the FDH mutation. “Two step” methods, in which the T4 analog never comes into contact with serum albumin owing to a wash step immediately after capture, avoid this problem. Such assay methods are expected to give FT4 results within the reference interval in FDH patients, but this expectation has been questioned (1)(2). Thyroid-function tests, including 1- and 2-step methodologies, were examined in 4 affected individuals from different families who had their FDH diagnoses proved genetically …

Role of autoimmune and familial factors in goiter prevalence. Studies performed in a moderately endemic area.

The goitrogenic role of autoimmune phenomena in endemic goiter is still uncertain. Scanty and discrepant results have been reported in different areas of the world. This prompted us to evaluate the prevalence of circulating thyroid antibodies in an area of North-Western Tuscany during a survey for endemic goiter. The survey was carried out according to the P.A.H.O. criteria in a stable community. In all schoolchildren (n = 142, age range 7–15 yr) and in most of their parents (n = 159), thyroid size was evaluated and urine was collected for iodine determination. Blood was drawn for determination of circulating thyroid microsomal (MAb) and thyroglobulin antibodies (TgAb), TT3, TT4 and TSH. Prevalence of goiter in schoolchildren was 77.9% and 94.8% in their parents. Mean (± S.D) urinary iodine excretion was 55.0 ± 2.1 μg/24h. The overall frequency of TgAb and MAb in the adult population was 14.4%, statistically higher than that of control subjects matched for sex and age. The frequency in schoolchildren was 4.3%. The presence of goiter in children was unrelated to the presence of thyroid antibodies in parents, whether goitrous or nongoitrous. A higher prevalence of goiter was found in children with goitrous parents as compared to children with nongoitrous parents (p < 0.005). In conclusion, the frequency of thyroid autoantibodies in the adult population of the endemic area studied was increased, but showed no relation with the presence of goiter. The prevalence of goiter in children was associated with the presence of goiter but not of thyroid autoantibodies in parents. These data suggest that autoimmune phenomena are of limited importance in the development of endemic goiter.

Detection and characterization of autoantibodies blocking the TSH-dependent cAMP production using FRTL-5 cells

Autoantibodies blocking the TSH-stimulated cAMP production (TBkAb) were measured in immunoglobulin G (IgG) preparations from 38 patients with primary autoimmune hypothyroidism, using FRTL-5 cells. TBkAb were detectable in 15/23 IgG preparations from patients with untreated idiopathic myxedema, and in 2/15 IgGs from patients under L-thyroxine treatment. None of the IgG from 22 normal subjects or from 10 patients with nonautoimmune hypothyroidism following total thyroidectomy caused any significant effect on the TSH-stimulated cAMP production. No correlation was found between TBkAb and the thyroid microsomal antibody. Antibodies inhibiting the 125I-TSH binding to TSH receptor were detectable in only 3/20 patients; IgGs from these 3 patients were also positive in the TBkAb assay. One IgG with potent TBkAb activity inhibited the TSH-stimulated adenylate cyclase in a competitive manner, while it had no effect on the forskolin-stimulated cAMP production. The inhibiting action of this IgG was almost completely lost after preabsorption with human thyroid membranes. In conclusion, we describe a new practical and sensitive method for the measurement of TBkAb; TBkAb are distinct from the microsomal antibody, and are probably directed to the TSH receptor.