Effects of selenium supplementation on the natural course of autoimmune thyroiditis: a short review.

Selenium (Se) is an important element that exerts its effects on the selenoproteins. It is an essential component of the glutathione peroxidase enzymes, which have anti-oxidant and anti-inflammatory properties, and a component of iodothyronine selenodeiodinases, which catalyze the extrathyroid production of T3 from T4. Se is important to several aspects of thyroid homeostasis and may influence the natural course of thyroid diseases such as autoimmune thyroiditis (AIT). This review analyzes the effects of Se supplementation in patients with AIT, based on the studies published on this issue to date.

Restricted intraindividual urinary iodine concentration variability in nonfasting subjects.

OBJECTIVE: Individual urinary iodine concentration (UIC) reflects iodine intake over a short time prior to sampling. Since eating habits are relatively constant in single subjects, UIC should be relatively constant in a given individual. The aim of our study was to verify this hypothesis by assessing UIC in repeated single urine samples from a group of healthy subjects. DESIGN AND SETTING: A prospective sequential investigation was performed in 131 volunteer health workers or students recruited in our University hospital. INTERVENTIONS: Single urine samples were taken in a nonfasting state, between 0900 and 1100 hours. Group 1 was composed by 131 subjects who collected one urine sample. Group 2 was composed by 11 subjects of the group 1, who collected multiple repeated urine samples (as a whole 158 urine samples, mean 14 samples each). UIC mean+/-s.d., median and coefficient of variation (CV%) was measured in both groups. RESULTS: Interindividual UIC variation was wide, UIC ranging from 21 to 382 microg/l, mean 136+/-84 microg/l, median 124 microg/l, CV 62%. Also in the 11 subjects repeatedly sampling there were considerable differences among individual UIC average levels (ranging from 37+/-15 to 221+/-91 microg/l). However, in this second group, the intraindividual variation was considerably restricted (CV% 36). CONCLUSIONS: The present study shows that in a nonfasting state in mid-morning UIC is more stable from day to day in a single subject, depending on his eating habits, than in various subjects. Thus, a single urine sample even in nonfasting state may give some rough information about the individual's iodine status.

TSH levels and TSH response to TRH as a guide to the replacement treatment of patients with thyroid carcinoma.

Forty-six patients whose thyroid glands had been ablated for thyroid carcinoma, maintained on replacement treatment with triiodothyronine (T3), have been followed by means of serial determinations of pituitary thyrotropin (TSH) levels and of the TSH response to thyrotropin-releasing hormone (TRH), in order to verify the actual dose required to suppress TSH secretion. The treatment was begun with a dose of T3 roughly related to body weight (about 1 mug/kg/day). The daily dose was sequentially adjusted according to the measured TSH levels. The dose of T3 which reduced serum TSH within the normal limits varied from 40 to 120 mug daily. More precisely, it was as low as 40-50 mug daily in five patients and as high as 90-120 mug daily in three patients. The dose, which was given according to their body weights, varied from 0.75 to 1.12 mug/kg/day. TRH administration produced a marked increase of TSH levels in those patients whose TSH was elevated, and varying responses (from no response to a response three times the normal one) in those patients whose TSH was within the normal limits. In the latter group of patients, an increase of the T3 dosage inhibited the TSH response to TRH. These data suggest that, even though 1 mug/kg/day is an adequate T3 dose for the great majority of patients, the extent of TSH suppression is not surely predictable, but must be evaluated case by case by means of serial determinations of TSH levels and of the TSH response to TRH.

A novel mutation in the thyrotropin (TSH) receptor gene causing loss of TSH binding but constitutive receptor activation in a family with resistance to TSH.

Resistance to TSH is a syndrome due to reduced responsiveness of the thyroid gland to biologically active TSH. Inactivating mutations of the TSH receptor (TSH-R) have been detected in several cases of resistance to TSH, both partial and complete, sporadic and familial. In this study, we describe a family with the presence of resistance to TSH responsible for euthyroid hyperthyrotropinemia in two siblings from consanguineous parents. By direct sequencing of the TSH receptor gene, we identified a new mutation responsible for the substitution of an arginine with a cysteine at position 310, in the extracellular domain of the TSH-R. The mutation was homozygous in two brothers; heterozygous in both parents, an uncle, and an unaffected brother; and absent in the other unaffected brother. When stably transfected in Chinese hamster ovary cells, the Cys310 mutant TSH-R showed loss of response to TSH in terms of cAMP stimulation. However, a constitutive activity in terms of basal cAMP production was detected in the Cys310 mutant, compared with the wild-type TSH-R. Our data suggest that such a Cys310 TSH-R mutant may determine both the TSH resistance and the clinical euthyroidism detected in this family.

Effects of dextro-thyroxine, a preparation almost free of levo-thyroxine, on thyroid function, serum lipids and apolipoprotein A-I in "double pre-beta lipoproteinemia".

Eight subjects, belonging to a large family kindred repeatedly showing the electrophoretic pattern of the "double pre-beta lipoproteinemia", were studied. In seven of them thyroid function, serum lipids and apolipoprotein A-I were determined before and after treatment with dextro-thyroxine, preparation almost free of levo-thyroxine. In most of the patients, total-T4 levels and free-T4 Index were in the lower normal range, but basal TSH levels and the TSH response to TRH were normal. Dextro-thyroxine was effective in reducing both serum total cholesterol and triglycerides, but the percentage decrease in serum triglycerides was definitely greater than that of serum total cholesterol. This marked, unexpected hypotriglyceridemic effect is similar to that observed in a group of obese, hypertriglyceridemic hypothyroid patients treated with levo-thyroxine. Besides serum total cholesterol and triglycerides, the VLDL cholesterol/triglycerides ratio and the electrophoretic "slow moving" pre-beta component were also significantly reduced after treatment, suggesting that dextro-thyroxine can remove efficiently "remnant" VLDL particles from the plasma. Following dextro-thyroxine therapy, the relatively low pretreatment values of apolipoprotein A-I were significantly increased, being restored to normal.

Clinical meaning of circulating antithyroglobulin antibodies in differentiated thyroid cancer: a prospective study.

In recent studies of patients with differentiated thyroid cancer (DTC), an association between the persistence of tumor and the presence of circulating anti-thyroglobulin antibodies (TgAbs) have been described. The aim of the present study was to evaluate TgAb variations before and after total thyroid ablation and to correlate TgAb levels to the outcome of disease. Forty-three patients with DTC were studied (35 female, 8 male; 33 patients had papillary cancer and 10 follicular cancer). Tumor was intrathyroid in 20 cases, had spread to the lymph nodes in 19 and to the lungs in 4. All patients underwent total thyroidectomy and 131I therapy, and were then treated by suppressive doses of L-thyroxine. After a mean follow-up of 3.55 yr, TgAbs became undetectable in 24 patients (all were considered tumor-free), whereas TgAbs remained elevated in 19 cases. In 5 of these 19 patients, disease progression or persistence was documented (to the lymph nodes in three and to the lungs in two). TgAb levels were higher in patients with persistent disease in comparison with those tumor-free. Serum thyroglobulin (S-Tg) results were only elevated in the two patients with persistent disease in the lungs. Our data suggest that TgAbs determination may give some additional information to the follow-up of patients with DTC: the disappearance of TgAbs after therapy seems to represent a favorable prognostic factor, while the persistence of circulating TgAbs, particularly at high levels and in the absence of detectable S-Tg, may be representative of disease.

Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables.

We studied 134 patients with differentiated thyroid cancer and pulmonary metastases. All were treated with total or near total thyroidectomy, radioiodine and L-thyroxine. The prognostic value of the following variables in three groups of patients were evaluated by univariate and multivariate analysis: age at diagnosis, sex, histologic type, tumor extension, cervical lymph node metastases, mediastinic metastases, presence of metastases in distant sites other than lungs (multiple distant metastases) and morphological (chest x-rays) and functional (131I uptake) features of lung metastases. Univariate analysis identified patient age (p < 0.0001), morphological and functional features of lung metastases (p < 0.0001), presence of multiple distant metastases (p < 0.0001) and histologic type (p = 0.04) as significant prognostic factors. Multivariate analysis showed only morphological (p = 0.0014) and functional (p < 0.0001) features of lung metastases and the presence of multiple distant metastases (p = 0.01) as significant and independent variables. The data show that early (pre-radiological) scintigraphic diagnosis and 131I therapy of lung metastases appear to be the most important elements in obtaining both a significant improvement in survival rate and a prolonged disease-free time interval in these patients.

Germline and somatic mutations of the RET proto-oncogene in apparently sporadic medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) occur sporadically or as part of inherited multiple endocrine neoplasia (MEN) type 2 syndromes. To recognize misdiagnosed familial cases and to establish the frequency of somatic mutations, a series of 50 patients, clinically diagnosed with sporadic MTC, were analyzed for mutations in the RET proto-oncogene. The clinical management of the patient and of the family is different in the two cases. Germline mutations were detected in three independent cases, demonstrating that they were associated to familial MTC. The mutations affected exon 11 in two cases and exon 14 in one case. Somatic mutations were detected in eight patients (30%) and they were indicative of sporadic MTC. In seven cases the mutation affected codon 918 of exon 16 and in one case codon 634 in exon 11. No RET mutations were detected in the remaining patients. A different genetic and clinical management is proposed for individuals with a diagnosis of familial or sporadic MTC.

Medullary thyroid carcinoma: clinical features and long-term follow-up of seventy-eight patients treated between 1969 and 1986.

This article describes the findings of a retrospective analysis of data obtained on 78 patients with medullary thyroid carcinoma (MTC), recorded between 1969 and 1986, and then followed at the Thyroid Center of Padua (Italy). The ages of the patients ranged between 15 and 89 years, with a median age of 45. The female to male (F:M) ratio was 2.9:1. All patients except 2 had total thyroidectomy. In 70 cases the tumor was of sporadic type; there were 3 familial non-multiple endocrine neoplasia (MEN) MTC; 3 MEN IIa; and 2 MEN IIb. The median duration of follow-up was 15.9 years (13 patients were followed up between 15 and 20 years, and 9 longer than 20). At diagnosis, the tumor was intrathyroid (stage I and II) in 31 patients, with local lymphnodes involved (stage III) in 41 patients, and with distant metastases (stage IV) in 6 patients. A total of 34 patients died (4 were at stage II at diagnosis, 26 at stage III, and 4 at stage IV); 4 of them died of unrelated causes, the others with tumor. The median survival rate of the deceased patients was 6 years (41% of these patients died within 3 years and 24% after more than 10 years); 76% of the deceased patients were older than 45 years at diagnosis. A total of 44 patients are still alive, 22 are alive free of disease (with follow-up between 10 and 24 years, median 14.2 years) and 22 are alive with disease (median follow-up 12.2 years). Only 30% of the patients of both these groups was older than 45 years at diagnosis. Survival is strongly related to tumor stage and to age at diagnosis, because only 8 of the 34 deceased patients were younger than 45 years (and 2 of them died of unrelated causes); moreover, patients who were treated at earlier stages of the disease had better prognosis. Survival rate at 10 and 20 years was 95% for patients with tumor limited to the thyroid, whereas it was 55% and 28.6%, respectively, for patients at stage III and IV. Bone metastases were correlated with worse prognosis than distant metastases only to soft tissues. The sex did not affect survival. None of the patients who had postoperative low serum calcitonin (CT) levels and no response to pentagastrin stimulation showed recurrences in the follow-up. In patients with postoperative elevated serum CT levels, recurrences of the tumor increased over time. However, 30% of these patients continued to show only elevated CT levels without evidence of the disease, even after 15 years.

Serum thyroglobulin measurements in differentiated thyroid cancer.

In pathological states, the serum thyroglobulin (Tg) concentrations are generally high. Therefore, a serum assay of Tg levels is not useful for the differential diagnosis between benign or malignant disease in the preoperative period. Serum Tg measurements are a suitable marker in the follow-up of patients with differentiated thyroid carcinoma (DTC) during the postoperative period. After total thyroidectomy, serum Tg concentrations were found to be undetectable in subjects without evidence of residual thyroid tissue or metastases; however, detectable serum Tg levels in subjects on and off thyroid hormone suppressive therapy indicate the presence of residual or metastatic thyroid tissue. An increase in serum Tg levels during thyroid stimulating hormone (TSH) suppression indicates that further investigations are necessary.

Favorable long term results in patients with small differentiated thyroid cancer not treated with radioiodine.

Data on a group of 110 patients with differentiated thyroid cancer not treated by radioiodine are reported. Most of them had intrathyroid (stage I) papillary or capsuled follicular cancer of less than 3 cm diameters. They all received thyroxine at TSH suppressive doses. The follow-up ranged between 4 and 25 years, mean 8.7. No patient died of tumor. Two very old patients died free of disease. Four recurrences occurred, within 8 years, all in patients over 45 years, all local or nodal, all papillary, 3 out of 4 after total thyroidectomy. This study shows that radioiodine therapy may be avoided and that lobectomy may be sufficient in patients under 45 years with small papillary or capsuled follicular cancer.

Prognostic value of early postoperative calcitonin level in medullary thyroid carcinoma.

AIMS: Serum calcitonin (CT) assay is commonly used in the diagnosis and follow-up of medullary thyroid carcinoma (MTC). The aim of this study was to ascertain whether serum CT levels, measured in the first few days after surgery, could be used to evaluate the efficacy of treatment. METHODS: A group of 33 patients was studied. In all patients the follow-up was more than 20 months. RESULTS: Preoperatively basal CT serum levels were high in all patients. Twenty-four hours after surgery CT serum levels dropped to within the normal range in 8 patients and 72 hours after operation in 7 others. In this group 1 patient was at stage I, 11 at stage II and 3 at stage III. Basal and pentagastrin stimulated CT levels continued to be in the normal range in these 15 patients 6 and 12 months after surgery and at the subsequent year by follow-up visits. No clinical or radiological evidence of disease was found during the follow-up in this group. In the other 18 patients CT was reduced but still high 72 hours after surgery; 6 months later basal serum CT levels continued to be elevated or responsive to pentagastrin stimulation. In this group restaging showed tumor relapse in the thyroid bed in 2 patients, cervical lymphadenopathy in 11, and distant metastases (bone, liver) in 3. CONCLUSIONS: Immediate postoperative CT serum levels seem to be the most useful index to evaluate the efficacy of surgical treatment and the presence of residual neoplastic tissue.

The extent of surgery for thyroid medullary cancer.

AIMS: Evaluation of the impact of the extent of primary surgery and reintervention on the outcome of patients with medullary thyroid carcinoma. METHODS: Seventy-two patients with medullary thyroid carcinoma (MTC) were surgically treated between 1967 and 1992. RESULTS: Fifty-five cases were sporadic, 5 patients had MEN 2A, 4 MEN 2B syndrome and 8 familial non-MEN MTC; 1 patient had stage I disease, 30 patients stage II, 36 stage III and 5 stage IV. Sixty-four had their initial treatment at our center, and 8 came for subsequent treatment. At first treatment, 8 patients were subjected to partial thyroidectomy, 10 to total thyroidectomy, 53 to total thyroidectomy with neck dissection, and 1 to only radical neck dissection; postoperative serum calcitonin (Ct) levels returned to normal in 3, 6 and 27 patients, respectively. In the patient with only radical neck dissection, Ct levels remained elevated. No patient with Ct normalization after surgery became responsive to pentagastrin in the follow-up. Thirteen patients had a reoperation due to nodal relapse. At a mean follow-up of 5.7 years (6-252 months), the 10-year survival rate was 84.5% with a significant difference between patients under and over 40 years of age (96.4 vs 57%), between stage I-II (100%) and stage III, IV (83.8%, 0% respectively). At the last follow-up, 36 (50%) patients were alive and disease free and 26 were alive with disease (15 with distant metastases). Of the 10 deaths, 7 were due to tumor recurrence, 3 to 120 months after surgery. CONCLUSIONS: Data suggest that an earlier diagnosis rather than more extensive surgery could improve survival and reduce recurrences. However, the least treatment required is total thyroidectomy plus central neck and upper mediastinum clearance and in addition, according to the extent of nodal involvement, mono- or bilateral neck dissection. To avoid ineffective reoperation due to distant (mainly liver) micrometastases, persistent residual microscopic disease requires a more aggressive restaging.

[Goiter and iodine deficiency in Veneto: study on 6285 elementary and media school children]. / Gozzo e carenza iodica nel Veneto: studio su 6285 ragazzi delle scuole elementari e medie.

The aim of this paper was to determine goiter prevalence and urinary iodine excretion in the Veneto region. An extensive epidemiological survey was carried out in school-aged children visiting 6285 students and testing 1861 urinary samples. A goiter prevalence of 8.8% was found: 7.7% of grade 1A and 1.1% 1B; in the pre-mountainous area the prevalence was higher than 10% (11.7% in the Treviso and 12.7% in the Vicenza area). Urinary iodine excretion was less than 100 micrograms/Cr in about 45% of all examined children with a peak of 20% under 50 micrograms/Cr in the Vicenza district. According to the WHO criteria, the goiter prevalence in the Veneto can be considered under the limits of the epidemic standards. However the use of iodized salt seems advisable also in this area.

[Which thyroidectomy in Basedow disease?]. / Quale tiroidectomia per il morbo di Basedow?

One hundred and seventy patients with Graves' disease underwent thyroidectomy between 1987 and 1994 (10.5% of all thyroidectomies performed in the same period). Female/male ratio was 9/1; mean age 55.2 years and average period between diagnosis and surgical treatment 5.3 years. The average thyroid weight was 230 g (range 90-950 g). Thyroidectomy was subtotal in 110 and total in 60 patients, 5 of which had been previously treated elsewhere from 5 to 33 years before. Malignancy was incidentally found in 2.35% of patients. The complication rate resulted higher in total thyroidectomies than in subtotal procedures (bleeding 0.9% vs 5.4%, transient hypoparathyroidism 4.5% vs 12.7%, recurrent nerve lesion 0.45% vs 2.72%) however the differences were not statistically significant; this probably because both the procedures were carried out with the same technique for parathyroid gland and recurrent nerve safety. The need of repeated surgery increased the risk. In opposition to total thyroidectomy, subtotal thyroidectomy does not doom to complete and permanent replacement therapy (96.4% of hypothyroidism at 2 months, 72.6% at 4 years), but in this series it failed to achieve remission in 2 patients who maintained a mild hyperthyroidism and in one more patient who developed a relapse 4 years later. Serum TSI meaning is not clear, but preoperative positivity suggests a wider resection and postoperative persistence a closer follow-up by functional assessment. In conclusion surgical procedures for Graves' disease range from subtotal to total thyroidectomy but for a safe outcome the choice depends more on the intraoperative troubles of each single case than on theoretic advantages.

[Medullary thyroid carcinoma: prognostic factors]. / Carcinoma midollare della tiroide: fattori prognostici.

Fifty-one patients treated by total thyroidectomy plus nodal neck dissection of necessity for medullary thyroid carcinoma (MTC) with a minimum follow-up of 10 years (mean 14.5, max 22 years) were divided into three groups according to the outcome (alive disease-free; alive with disease; dead) and were compared in order to analyze the prognostic factors of MTC. Twenty years actuarial survival rate for age at diagnosis less than 50 years versus age over 50 (90% vs 45%) as well as for stage II versus stage III (85% vs 55%) was statistically different (p < 0.005 and p < 0.05 respectively). About 60% of recurrences were observed within 5 years after surgical treatment. Recurrence rate for stage III (70%) versus stage II (20%) was statistically different, but it was not for the age. Survival rate for patients with bony metastases (50% at 1 and 30% at 3 years) versus patients with other than bony metastases (100% at 10 years) was statistically different.

[Undifferentiated carcinoma of the thyroid gland]. / Il carcinoma indifferenziato della tiroide.

Anaplastic carcinoma of the thyroid is a tumour of advanced age, with a female/male ratio of 2/1. Its incidence is of 1-2 cases/million/year. The tumour is one of the most aggressive neoplasms affecting humans. It spreads very rapidly to the regional lymph nodes and causes distant metastases, in particular in the lungs and bone. Surgery, external radiation or chemotherapy are usually ineffective when used alone. Better results are obtained by combinations of these modalities, in particular by a combination of radiotherapy and chemotherapy followed by surgery. In our Centre we have, since 1991, adopted a multimodal treatment based on radiotherapy preceded by Cisplatin administration, followed by surgery and then by adjuvant chemotherapy with Adriamycin and Bleomycin. The initial results on a limited number of cases seem encouraging.

Iodine status in schoolchildren living in northeast Italy: the importance of iodized-salt use and milk consumption.

BACKGROUND: The aims of the study were: (i) to determine iodine status of schoolchildren living in northeast Italy; (ii) to assess dietary habits and iodine status and (iii) to investigate the level of knowledge concerning iodine sufficiency and ways to ameliorate iodine status. METHODS: One thousand three hundred seventy-five consecutive 12-13 year-old completed questionnaires collecting demographic data and information about the use of iodized salt and food frequency habits. Iodine concentration in urine samples (UIC) and in commercially available milk samples has been measured. RESULTS: The median UIC was found to be 81 µg/l (95% confidence interval (CI) 74-87); 40% of the subjects had an UIC of ≥ 100 µg/l. Iodine deficiency was prevalent in subjects living in hilly areas. Median iodine concentration in milk was 264 µg/l. Only the combined use of iodized salt plus daily milk normalized UIC, resulting into a median value of 108 µg/l. A logistic regression model confirmed independent associations between low UIC and low intake of milk, use of non-iodized salt and geographical location (P<0.0001). Only 45% of the subjects were aware of the importance of iodine. CONCLUSIONS: Northeast Italy is still characterized by mild iodine deficiency. An adequate iodine status was achieved only when iodized salt was combined with daily milk intake. The national iodine prophylaxis program has led to greater consumption of iodized salt and, it is now used in 60-70% of the Italian households. The low level of awareness highlights the need for public programs to promote knowledge and efforts to improve iodine status.