Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer.

We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.

Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients.

Familial medullary thyroid carcinoma only is related to germline mutations in the protooncogene RET, mainly in exons 10, whereas noncysteine mutations (exons 13-15) are considered infrequent. We analyzed 148 patients from 47 familial medullary thyroid carcinoma only families, and we found noncysteine RET mutations in 59.5% of these families. Of the index cases with noncysteine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference in size, bilaterality, presence of C cell hyperplasia, or nodal metastases was found. Gene carriers with noncysteine RET mutations had a lower incidence of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized at an older age. In conclusion, familial medullary thyroid carcinoma with noncysteine RET mutations are not infrequent and are overrepresented in presumed sporadic medullary thyroid carcinoma, suggesting that RET analysis should routinely be extended to exons 13, 14, and 15. The phenotype is characterized by a late onset of the disease, suggesting a delayed appearance of C cell disease rather than a less aggressive form. In familial medullary thyroid carcinoma gene carriers, the optimal timing for thyroidectomy remains controversial. Based on these data, we propose that surgery should be performed before elevation of the basal calcitonin level, potentially as soon as the pentagastrin test becomes abnormal.

Sporadic medullary microcarcinoma of the thyroid: a retrospective analysis of eighty cases.

Clinical characteristics and prognosis of 80 patients (53 women and 27 men) with sporadic medullary thyroid carcinomas (MTC), less than 1 cm in size (micro-MTC), operated on between 1971 and 1996 are reported (73 total and 7 partial thyroidectomies). These patients, obtained from a national database of 899 patients with MTC, were compared with 357 cases of sporadic MTC greater than 1 cm and 149 subjects with familial MTC less than 1 cm (familial micro-MTC). Median age at surgery was 52.5 years, a distribution similar to larger sporadic MTC. Micro-MTC was identified due to elevated calcitonin (47.5%), clinically identified lymph node (10.0%), distant metastases (6.3%) or pathologic finding at surgery (36.2%). Diarrhea and/or flushing were observed in 6 patients including 4 with clinically identified lymph node. Among patients who had lymph node dissection at surgery (68.8%), lymph node involvement with tumor was observed in 30.9%, and was significantly more frequent in multifocal (7/11) than in unifocal micro-MTC (p < 0.03). All sporadic micro-MTC were unilateral. Survival rate was 93.9% +/- 4.4% (SE) at 10 years, greater than that observed in sporadic macro-MTC (p = 0.04). Normal postoperative basal calcitonin (CT) was obtained in 71.1% of micro-MTC patients versus 33.6% in sporadic macro-MTC (p < 0.01). Sporadic micro-MTC is much more frequent than expected, 15% of MTC in our series. Although specific survival rate and percentage of biological cure in micro-MTC are significantly better than for larger tumors, the frequency of lymph node involvement, however, justifies an aggressive surgical approach including total thyroidectomy and bilateral central lymph node dissection.

The influence on thyroid function of two iodine-containing radiological contrast media.

The aim of this study was to establish the effects of two iodine-containing radiological contrast media (ioxaglate and diatrizoate) on plasma iodide, thyroid hormones and TSH in a group of 20 subjects (8 females, 12 males). The following were evaluated two, eight and 30 days after administration of the drugs: plasma iodide, T4, T3, rT3, FT41, TSH before and after TRH (250 micrograms IV). 131I uptake was measured before the media were given and 30 days afterwards. The results were compared at the different times during the investigation using Wilcoxon's signed ranking test for non-parametric variables. Plasma iodide was found to be above the normal range two to eight days after ioxaglate and two to eight and 30 days after diatrizoate. After ioxaglate, rT3 was increased at eight days and T3 at 30 days. 131I uptake remained low after the 30th day. After diatrizoate, T4 was decreased on the second day and FT41 was low, on the eighth and 30th day. All figures represent statistically significant but nevertheless minor variations of the initial value of each parameter. In conclusion, although ioxaglate and diatrizoate lead to variations in plasma thyroid hormone levels, they are of little importance.

[Interference of T4 in different serum T3 radioimmunologic determination kits]. / Etude de l'interférence de la T4 dans différents systèmes de dosages radioimmunologiques de la T3 sérique.

The cross reactivity of T3 antibodies for T4 was studied with five T3 RIA kits. T4 used was provided from T4 RIA Kits (Abbot Beckman, Corning). The results are shown on the table indicating the concentration of T3 or T4 required to displace 50% of the T3 125 from anti T3. The cross reactivity for T4 of T3 antibodies from Lepetit and Phadebas was the same and was smaller than cross reactivity with the other laboratories. In clinical practice serum T4 levels of hypo and euthyroid subjects are not so high to false T3 determination. In hyperthyroid subjects the diagnosis cannot be influenced by this cross reactivity. However, the study of the kinetic and monodeiodination of T4 into T3 may be wrong when T4/T3 ratio increases.

[Pathology of thyroid hormone receptors]. / Pathologie des récepteurs des hormones thyroïdiennes.

The syndrome of resistance to thyroid hormones may affect overall or only some tissues. The generalized resistance associates a familial eu or hypometabolic goiter, increased free thyroid hormones with normal or elevated plasma TSH levels. The inheritance of the disease is autosomal dominant in most of the patients. In vivo or in vitro tests may be used to assess the diagnosis. Therapy refers to high doses of T3 or T4. Pituitary resistance to thyroid hormones leads to hyperthyroidism with normal or high TSH levels. The treatment uses different TSH suppressive drugs. Peripheral resistance associates hypometabolism with normal T4-T3 secretion and needs high T3 doses for therapy. An inherited abnormality of T3 nuclear receptor seems to be the consequence of a mutant gene. Hypersensitivity to thyroid hormones associates hypermetabolism with low or normal free thyroid hormone levels and increased T3 nuclear receptors.

[The 20-minute iodine uptake in Graves' disease. 2. Natural course during medical treatment (author's transl)]. / Intérêt de la mesure porécoce de la captation de l'iode radioactif (20e minute) dans la maladie de Basedow. 2 : Evolution lors du traitement médical.

The early (20 min) radioiodine uptake has been used to monitor the fluctuations in disease activity among 35 Graves' disease patients treated for 18 months with carbimazole and T3. A wide variety of behaviour was observed. Although as a group the uptake tended to fall progressively with time, in some it fell only to rise again and in others it fluctuated erratically. The initial fall in uptake in a substantial minority of patients was sufficient to suggest that carbimazole may exert a fundamental and beneficial influence of the immunological disturbance in Graves' disease.

[The 20-minute iodine uptake in Graves' disease. 3. Prognostic value (author's transl)]. / Intérêt de la mesure précoce de la captation de l'iode radioactif (20e minute) dans la maladie de Basedow. 3 : Valeur pronostique.

The early (20-min.) radioiodine uptake was used to monitor disease activity in 35 Graves' patients undergoing an 18-month course of treatment with carbimazole and T3. T3 alone produced no change in uptake, but four weeks after the introduction of carbimazole, the mean uptake had fallen by more than 50%. Six months after completion of treatment, 20 patients (group R) had relapsed, and 15 (group E) were in remission. The only quantitative difference in mean uptake behaviour between R and E patients was one of degree, their slopes being parallel. Thus, while the mean uptake of both groups fell progressively towards normal, that of group E patients arrived much the earlier, and carbimazole seemed to hasten both. Major fluctuations in thyroid uptake were observed in most individuals, but certain defined patterns emerged. While the uptake suppressed at some time during treatment in 32 (91,4%) patients, remission was associated only with early (ie before month 5) and stable suppression. The predictive value of the uptake test early during treatment was limited to identifying a group certain to relapse, but these non-suppressors accounted for only 40% of all patients, and it was not possible to identify with any certainty those who would ultimately remit.

[The 20 min. iodine uptake in Graves' disease. 1. Technique and reliability (author's transl)]. / Intérêt de la mesure de la captation précoce de l'iode radioactif (20e minute) dans la maladie de Basedow. 1: Technique et fiabilité.

The 20 minute intravenous radioiodine uptake technique is described in detail and results compared with those from the classical 2 1/2 hour oral uptake in 93 Graves' disease patients. Two methods used in correcting for extrathyroidal radioactivity in the early uptake are similarly compared. The 20 minute uptake was normal (locally less than 8% dose) in only 6,5% of the patients while the 2 1/2 hour uptake was normal (locally less than 35% dose) in 18,5%; in six patients the uptake at 20 min. was higher than at 2 1/2 h, observations indicating the superior sensitivity and diagnostic value of the early uptake. The suppression test performed at 20 minutes was, furthermore, pathological in 97,8% of patients. The comparison of methods to correct for extrathyroidal radioactivity in the 20-minute test showed excellent agreement between thigh count subtraction and application of a formula based on the thyroid uptake at 2 minutes. The former technique, however, was considered to be simpler. We conclude that the 20 minute intravenous iodine uptake technique is not only simpler to perform than the classical oral method, but is also diagnostically more accurate. A high quality scan was obtained 30-60 minutes after the injection of radioiodine in most of these patients.

[The treatment of Graves' disease with antithyroid drugs and small doses of radioiodine (author's transl)]. / Traitement de la maladie de Basedow par l'association de faibles doses d'iode radioactif et d'antithyroïdiens de synthèse. A propose de 330 cas aven un recul de 20 ans.

Three hundred and thirty Graves' disease patients (258 F. 72 M. ; mean age = 50 +/- 07 years) were treated by 131I from 1961 to 1979 ; 57 % had a goiter and 32 % had exophthalmos. One or several doses of radioiodine were given to each patient without dosimetry. The mean total dose (+/- SEM) was = 8,51 +/- 0,44 mCi and the mean for the first dose 4,34 +/- 4 ans 54,8 % of the patients received only one dose but 10,3 % of them had more than 3 doses. Data obtained by actuarial methods showed 66 % of the cases to be in remission in less than 2 years ; the frequency of hypothyroidism increased steadily by 3 % every year to give 15 % at 5 years and 30 % at 10 years. Remission was slower to occur in goitrous subjects and hypothyroidism was less frequent in this group despite doses significantly higher of radioiodine (p less than 0,001). Recovery was also slower among exophthalmos patients. Finally, the mean 3-hour radioiodine uptake and plasma T3 level were significantly lower six months after the first therapeutic dose among those who were cured of thier hyperthyroidism within two years.

[Proceedings: Kinetics and disposal rate of triiodothyronine in patients with atuonomous hot nodular goiter, with or without thyrotoxicosis (author's transl)]. / Etude du métabolisme de la triiodithyronine au cours du nodule chaud autonome, avec ou sans hyperthyroïdie

Eight female patients are studied, four of them without hyperthyroidism. The following were measured before and after surgery = hormonal iodine by column, serum concentrations of T T3, AF T3, TSH, total T3 distribution space, T3 pool size T3 fractional turnover rate. T T3 is measured in the serum of peripheral venous blood, nodular venous blood and of jugular venous blood of the opposite side of the adenoma. Before surgery, the mean of T T3 in patients with hyperthyroidism is increased in serum obtained from brachial and not nodule venous blood. Are also increased AF T3 and T3 production rate. In patients without hyperthyroidism, T T3, AF T3 are increased in two subjects only, but T3 production rate is rised among three of them. After surgery the previous values are not different with normal values. These data are in good agreement with the hypothesis that, in patients without thyrotoxicosis, there is an increase in T3 production from not nodular goiter. There phenomena may explain unresponsiveness to TRH test and inactivity of normal thyroid. Absence of hyperthyroidism may be due to a lack of sensitivity of peripheral tissues to the increase of T3.

The TRG Test. Which is the best index of TSH release?.

Prolonged (two hours) TRH tests were performed on 29 controls and 182 thyrotoxicosis patients of varying thyroid status after treatment with radioiodine. The object was to find which of the simple measurements of TSH from the TRH test most faithfully reflected the total amount of TSH (TTSH) released in response to the TRH. The simple indices compared were the absolute levels of TSH (ATSH) achieved at intervals during the test, and the increments in TSH (delta TSH) recorded at the same points in time. TTSH was measured by planimetry of the area beneath the response curve. Patients were classified as normo-responders, hyper-responders or hypo-responders according to normal limits for TTSH deduced from the controls. When each simple index of TSH response was substituted in turn for TTSH, the overall frequency of misclassification was considerably greater for ATSH than for delta TSH. This was largely due to the wide variability of passive or basal TSH secretion, which seriously confused the distinction between normally-responsive and hypo-responsive patients when ATSH was used. The delta TSH measured at 30 minutes gave the best overall results in terms of least classification error and closest correlation with TTSH.

[Chronologic study of free T3 and T4, of responses to TRH and of the suppression test during treatment of Basedow's disease]. / Etude chronologique de la T3 et de la T4 libres, des réponses à la TRH et du test de freinage, au cours de la maladie de Basedow traitée.

32 patients with Graves' Disease were investigated before treatment, during ATD therapy and after recovery with a normal T3 suppression test. Before treatment, TRH response was negative with elevated values of plasma TT4, AFT4, TT3 and AFT3. The 3d, 6 - 9 and 12-18 months and after recovery, several patients remained unresponders to TRH despite normal AFT4 and AFT3 in serum. In an opposite way some patients were responders, 1 month after ATD withdrawal, at the 6-9 month, with elevated values of AFT4 or AFT3. The discrepancy between TRH response and T3 suppression test is pointed out after recovery. The unresponsiveness of TSH to TRH unexplained by serum AFT4 or AFT3 may be due to : 1) a decrease in pituitary TSH stores. 2) an unknown factor inhibiting TSH release during Graves' disease 3) an hypersensitivity of thyreotrop cells to T3.

[HLA B8 and Graves' disease (author's transl)]. / Système HLA et maladie de Basedow

HLA typing has been carried out in 100 caucasions with Graves' disease and compared with 270 healthy controls. 25 HL-A antigens were characterized using a lymphocytotoxicity micro-technique. Analysis of the results reveals an increased incidence of HLA-B8 antigen (35% in patients as compared to 16.3% in controls) with a high degree of statistical significance: p = 0.0002 and corrected p (X 25) = 0.005. We did not observe a clear-cut correlation between the presence of HLA-B8 and different characteristics of the disease: sex, age of onset, familial history, exophtalmia, goiter, severity. The knowledge of the relationships between the HLA B8 gene and several auto-immune diseases is a strong argument in favor of the auto-immune nature of Graves' disease. The association between HLA B8 and Graves' disease could be explained by a close linkage between the second HLA locus and one or several Ir-IrG loci, occupied in predisposed individuals by "predisposing" alleles. In these subjects, an antigenic contact with an exogenous etiological agent would induce a pathological immune response, with production of thyroid stimulating IgG.

[Study of the HL-A system in Basedow's disease (author's transl)]. / Etude du système hla au cours de la maladie de basedow

HL-A typing has been carried out in 100 caucasians with Graves' disease and compared with 270 healthy controls. 25 HL-A antigens were characterized using a lymphocytotoxicity microtechnique. Analysis of the results reveals an increased incidence of HL-A8 antigen (35% in patients as compared to 16,3% in controls), with a high degree of statistical significance: p=0.0002 and corrected p X 25) = 0.005. We did not observe a clearcut correlation between the presence of HL-A8 and different characteristics of the disease: sex, age of onset, familial history, exophtalmia, goiter, severity. The knowledge of the relationships between the HL-A8 gene and several auto-immune diseases is a strong argument in favor of the auto-immune nature of Graves' disease. The association between HL-A8 and Graves' disease could be explained by a close linkage between the second HL-A locus and one or several Ir-IgG loci occupied in predisposed individuals by predisposing alleles. In these subjects, an antigenic contact with an exogenous etiological agent would induce a pathological immune response, with production of thyroid stimulating IgG.

[Long term follow up of medical treatment of differentiated thyroid cancer]. / Contrôle à long terme du traitement médical du cancer thyroïdien différencié.

106 patients, 114 W, 27 M, were thyroidectomized for differentiated thyroid cancer (follicular 29.3%-papillary 54.3%) with different stages of gravity (NO: 48.2% - N1: 32.8% - N2: 19%). Neck dissection was used in cases of involved nodes. One or several doses of 131 I were given to 126 subjects, 106 patients were treated with LT4 (mean daily dose: 2.5 micrograms/kg BW). 23 patients presenting intolerance to LT4 with non suppressed TSH for 13 of them were treated by an association of TRIAC + LT4. The follow up included a yearly check up involving clinical examination, plasma Tg and TSH assessment, neck ultrasonography and X-ray of the chest. Therapy was stopped for 4 weeks in cases with Tg above its detectable value and a total body scan performed with Tg and TSH controls. The mean duration of follow up was 94.5 +/- 67.7 months and extended to more than 5 years for 61% of the patients. We observed 22 relapses of the tumor with 4 deaths. Age less then 45 years, appears as the best factor of prognosis. 2 groups of patients were compared to evaluate the incidence of TSH suppression on the relapse free survival (group 1 n = 30 with a TSH < or = 0.10 mU/l and group 2 n = 15 with a TSH always > 1 mU/l during the follow up). The relapse free survival was shorter in group 2 (p = 0.01). Association of TRIAC with LT4 leads to a reduction of the daily dose of LT4 (m = 25 micrograms/day) with a significant improvement of TSH suppression and clinical tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Value of triiodothyroacetic acid as suppressive treatment of the thyrotropin secretion in thyroid pathology]. / Intérêt de l'acide triiodothyroacétique comme traitement freinateur de la sécrétion thyréotrope en pathologie thyroïdienne.

Fifty-six patients were treated with triiodothyroacetic acid (TRIAC) for its suppressive effect on the pituitary-thyroid function. Thirty of these patients had undergone partial thyroidectomy for benign goitre, and among these 14 had developed hyperplasia of the remaining thyroid tissue (group I); 18 presented with homogeneous or nodular goitre (group II); 8 had been thyroidectomized for carcinoma (group III). Before TRIAC was prescribed, thyroid hormones had been used in 33 patients, exerting a suppressive effect on the thyrotropic hormone in 4 patients of group III and producing signs of intolerance in 24 cases. TRIAC was administered in doses of 700-1,750 micrograms/day to all patients of group I and II, and combined with LT4 100 micrograms/day to group III patients. Suppression of the thyrotropic secretion was obtained in all group III patients and in 88 p. 100 of groups I and II patients. Thyroid gland hypertrophy regressed or disappeared in 21 patients of groups I and II, and no relapse or metastasis was observed in group III. TRIAC was well tolerated in all but one patients.

[Study of discrepancies between "ultra-sensitive" TSH and thyroid hormones levels]. / Etude des discordances entre les taux de TSH "ultra-sensible" et d'hormones thyroïdiennes.

TSH levels were determined by "ultra-sensitive" assay (TSH-US) in 1300 sera and compared to thyroid hormone (TH = TT3 and FT4) values. Discordant results were observed in 186 cases divided into 3 groups according to TSH-US and TH values. Clinical data obtained in discordant cases showed that most of the subjects (75%) were under treatment (antithyroid drugs, suppressive or replacement hormone therapy) or had been treated by surgery or 131I when the sera were drawn. Among the patients who had not been treated (25%) we found moderate or subclinical hyperthyroidism (toxic adenoma or goitre) or hypothyroidism. In conclusion, most of the discordant results proved consonant when the clinical or therapeutic data were taken into account.

[Incidence of endemic goiter on Reunion Island. A search for etiological factors]. / Incidence du goitre endémique à l'île de la Réunion. Recherche des facteurs étiologiques.

In an epidemiological study carried out in Reunion Island, 1,686 randomized school children aged from 11 to 15 years were examined for goitre by cervical palpation. A detailed questionnaire was fully completed by each child and his parents. The iodine level was measured in 168 urinary samples and in the salt and water consumed in the various places investigated. The overall incidence of goitre was 8.2 percent, rising up to 19.7 percent in the mountainous part of the island. The mean urinary iodine level was 40.2 +/- 2.7 micrograms I/g creatinine (m +/- SEM) and fell to 20.0 +/- 3.7 in the highlands. Water and salt contained little iodine. A significant relationship was noted between the presence of goitre on the one hand and sex, familial incidence of goitre, cassava consumption and distance from the coast on the other hand. This study demonstrates that endemic goitre and iodine deficiency are present in a limited area of Reunion Island.

[Endemic goiter in the La Kara region (Togo). Analysis of etiologic factors]. / Etude du goitre endémique dans la région de La Kara (Togo). Analyse des facteurs etiologiques.

Among 6,035 people living in 3 villages from the area of La Kara (Togo), 984 randomized subjects were investigated to evaluate goiter prevalence and related etiologic factors. Creatinine and thiocyanates (SCN-) were measured in urine, thyroid hormones and TSH in plasma. Iodine was evaluated in urine, water, salt, soil, millet and sorgho. The amount of cassava was evaluated in food. Mean goiter prevalence was 32%, reaching to 45.9% in one village; urinary iodine remained in a low range (27.2 +/- 2.18 micrograms/g creatinine in adults, 34.3 +/- 6.7 in children--m +/- SEM) independently of the presence of endemic goiter. Urinary SCN- was increased. Low iodine values were found in food, salt, soil and water which contained few mineral elements except flour which was increased in the samples collected in one of the 3 villages. Cretinism was absent, T4, T3, TSH remained in a normal range. This study confirms a high prevalence of endemic goiter in the area of La Kara with iodine deficiency, leading to an urgent iodine supplementation.