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.

Human anti-thyroid peroxidase single-chain fragment variable of Ig isolated from a combinatorial library assembled in-cell: insights into the in vivo situation.

In an attempt to explore the natural variable heavy and light chain (VH/VL) pairing of autoantibodies involved in Graves' disease, we constructed a phage-displayed Ab library obtained by in-cell PCR of thyroid-infiltrating cells. We report here the molecular cloning and characterization of human single-chain fragment variable regions (scFv) specific for thyroid peroxidase (TPO) generated from this library. On the basis of the nucleotide sequences, three different scFvs were obtained (ICA1, ICB7, and ICA5). All were encoded by genes derived from the VH1 and Vlambda1 gene families. Using BIACORE for epitope mapping and kinetic analysis, we showed that these scFvs exhibited high affinity (Kd = 1 nM) for TPO and recognized three different epitopes. The biological relevance of these scFvs as compared with serum anti-TPO autoantibodies was assessed by competition studies. Sera from all the 29 Graves' disease patients tested were able to strongly inhibit (60-100%) the binding of the 3 scFvs to TPO. These data demonstrate that the in-cell PCR library generated human anti-TPO scFvs that retained the VH/VL pairing found in vivo and that the different epitope specificities defined by these scFvs overlapped with those found in the sera of patients with autoimmune thyroid disease.

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.

TSH suppression combined with carbimazole for Graves' disease: effect on remission and relapse rates.

OBJECTIVE: We studied the influence of TSH suppressive therapy combined with carbimazole (CBZ) on treatment outcome in Graves' disease. DESIGN: Open non-randomized prospective study. SETTING: University Hospital of Montpellier, France. SUBJECTS: Sixty-six consecutive patients without prior treatment were included. All the patients were treated initially with 30 mg of CBZ. After 1 month of treatment, one group continued CBZ alone (n = 23), another group received a combination of CBZ plus T3 (n = 19) and a third group received CBZ and 3,5,3'-triiodothyroacetic acid (Triac, n = 24). Therapy was stopped when remission was obtained based on clinical euthyroidism, normalization of FT4 and of early radioiodine uptake. Nine patients with medical treatment failure or major side effects requiring to stop antithyroid drugs underwent surgery or radioiodine therapy. Nine patients were lost to follow-up. The remaining 48 patients were available for analysis of both remission and relapse. RESULTS: The median duration of therapy was 18 months (range, 4-41 months). Based on clinical examination, goitre size at 4 months decreased more in the CBZ + T3 and CBZ + Triac groups than in the CBZ group (P = 0.02). The overall remission rate tended to be higher in the groups treated with CBZ + T3 and CBZ + Triac than in the group treated with CBZ alone, but the difference did not reach statistical significance (P = 0.17). No difference in the relapse rate was observed between the three groups. CONCLUSION: TSH suppression combined with CBZ has little or no effect on remission and relapse rates in Graves' disease patients.

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.

[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)

[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.

Thyroid hormone generalized resistance.

The syndromes of thyroid hormone resistance may affect overall or only some tissues. The generalized resistance is an inherited disease which involves a familial eumetabolic or hypometabolic goiter, increased free thyroid hormones with normal or elevated plasma TSH levels; children may present mental retardation, deafness, short stature and delayed bone age. The disease is frequently misdiagnosed. In vivo and in vitro tests may be used to assess the diagnosis. The defect of increment of sex hormone-binding globulin after administration of T3 may be useful in the demonstration of the disease. Therapy uses high T4 or T3 doses in hypometabolic patients. The generalized thyroid hormone resistance could be linked to abnormalities at the T3 receptor and c-erb A gene level, as a consequence of different point mutations or deletions involving the hormone-binding domain.

[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.

[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.

A case of hypersensitivity to thyroid hormones with normally functioning thyroid gland and increased nuclear triiodothyronine receptors.

A 52-year-old male presented himself with tachycardia crises which appeared first during childhood, increased in frequency without goiter or exophthalmos. Cardiac and adrenergic diseases were excluded. The thyroid function was normal regarding T4, free T4 and T3, TBG, radioiodine uptake, TSH and T3 suppressibility; however the TSH response to TRH was decreased. The lymphocyte nuclear T3 receptor was found with an affinity close to that of normal volunteers (Ka: 1.42 x 10(10) M-1 vs 1.95 +/- 0.35 x 10(10) M-1) and a binding capacity markedly increased (9.9 vs 3.7 +/- 0.4 fmol T3/100 micrograms DNA). Pindolol was inefficient on the dysrhythmia which disappeared with carbimazole and relapsed after withdrawal of the antithyroid drug. Under carbimazole, the plasma T4 markedly decreased (27.7 +/- 3.6 nmol/l) but the patient remained euthyroid. The clinical course and the laboratory data suggest that the tachycardia crises are the consequence of a hypersensitivity of the heart to thyroid hormones, associated with an increased number of T3 nuclear receptor sites in lymphocytes.

Multi-center study of a new technique for measuring free thyroxin in serum.

In a multi-center trial we evaluated the accuracy of a new assay kit for free thyroxin (T4), the Behring free T4 RIAgnost, in 1036 subjects: 379 normal subjects, 536 patients with thyroid dysfunction, and 121 subjects with no thyroid dysfunction but with conditions that potentially could interfere with the assay. The kit combines immunoextraction and the use of a modified tracer. Although some limitations remained in using a direct assay method for free T4 in certain nonthyroid conditions, this test was superior to one based on the use of a T4 analog. This kit seems to be very accurate for the diagnosis of untreated thyroid pathologies.

The management of differentiated thyroid cancer in Europe in 1988. Results of an international survey.

In order to know how thyroid nodules and differentiated thyroid cancers are investigated and treated in 1988, an international inquiry was performed by mean of a questionnaire based on a well-defined case report of a 35-year-old female with a solitary small thyroid nodule. Clinicians were asked to indicate their diagnostic and therapeutic approaches to the reported case and to some variations. Analysis of the 157 responses from thyroid experts showed that three in vitro tests (sensitive-TSH, free T4 and total T4) and three in vivo tests (99mTc or radioiodide scintiscan, fine needle aspiration and ultrasonography) were performed most frequently. In the case of a solid and cold nodule and in the absence of fine needle aspiration results, 19% of respondents advocated suppressive therapy and 81% surgery. In the same clinical case, but whom fine needle aspiration had been performed and cytology was benign, surgery was advocated by 24%, suppressive therapy by 48% and a regular follow-up without treatment by 28% of respondents. When surgery was performed and the diagnosis was a differentiated thyroid cancer, (near) total thyroidectomy was more frequently chosen than partial thyroidectomy in both papillary (60 and 40%, respectively, of respondents) and follicular (74 and 26%, respectively, of respondents) cancers; 80% of clinicians did not change their surgical technique in relation to histological type of the tumour. Total thyroidectomy was more often recommended in most of the clinical or anatomical variations compared with the basic case report. Pre- or postoperative hormonal therapy was initiated with L-T4 and TSH suppression was controlled by sensitive-TSH and thyroglobulin determinations. After total thyroidectomy, 131I was used with similar modalities for papillary and follicular cancers to ablate a thyroid remnant.

Novel immunoradiometric assay of thyroglobulin in serum with use of monoclonal antibodies selected for lack of cross-reactivity with autoantibodies.

A multisite immunoradiometric assay for measurement of serum thyroglobulin (Tg), designated Magnogel-IRMA-Tg, has been developed, involving magnetic microbeads (Magnogel). This assay is based on the use of five anti-Tg monoclonal antibodies (MAbs) directed against three antigenic regions on the Tg molecule that are not recognized by anti-Tg autoantibodies (aAbs). Four of these MAbs, directed against two antigenic domains, were coupled to the magnetic beads and were used to trap the serum antigen. Another MAb, directed against the third region, was iodinated and served as the labeled second antibody. The Magnogel-IRMA-Tg technique is reproducible, rapid, and sensitive (lower detection limit, 3 micrograms/L). The assay reliably measures serum Tg in the presence of anti-Tg aAbs.

[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.

Antigenic domains on the human thyroglobulin molecule recognized by autoantibodies in patients' sera and by natural autoantibodies isolated from the sera of healthy subjects.

We determined the regions on the human thyroglobulin (hTg) molecule recognized by anti-hTg autoantibodies (aAbs) in the sera of patients with Hashimoto's thyroiditis, Graves' disease, and thyroid carcinoma and by anti-hTg natural aAbs isolated from the sera of healthy subjects. Fifteen anti-hTg monoclonal antibodies (MAbs) directed against six distinct antigenic regions were used for this study. The anti-hTg aAbs in the patients' sera recognized mainly region II and occasionally region IV. The natural aAbs were present in the serum at low concentrations; consequently, we isolated and concentrated them for this investigation. The isolated natural aAbs inhibited the interaction of the anti-hTg MAbs with the majority of the antigenic regions identified. Region II was not well recognized, however, by these natural aAbs. This difference in specificity between the anti-hTg aAbs and the anti-hTg natural aAbs may have diagnostic significance.