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The aim of this study was to assess the prognostic factors for treatment efficacy, and in particular the increase in serum thyroglobulin (Tg) level at the time of the first ablative radioiodine treatment, in patients with differentiated thyroid carcinoma (DTC).A retrospective chart review was performed on 407 patients treated for DTC by total thyroidectomy and (131)I ablation between 1995 and 2002, and examined 5-12 months later with diagnostic (131)I whole-body scan and serum Tg measurement after thyroid hormone treatment withdrawal. At the time of the ablative radioiodine treatment, serum Tg level was determined just before (131)I administration (TgD0) and 5 days later (TgD5); Tg variation was expressed as the ratio TgD5/TgD0. At the first post-ablation follow-up examination, unsuccessful ablation was defined by a Tg levelor =2 ng/ml and/or abnormal (131)I uptake.Ablation was unsuccessful in 51 patients. Univariate analysis showed high TgD0 level, low TgD5/TgD0 ratio extrathyroidal invasion, (131)I uptake in the neck (excluding the thyroid bed) during the ablative treatment and distant metastases to be significantly associated with unsuccessful ablation. On logistic multivariate analysis, TgD0 level5 ng/ml and TgD5/TgD0 ratioor =20 were independently associated with successful ablation. A receiver operating characteristic curve analysis determined that a TgD5/TgD0 ratio greater than 20 had a 97% positive predictive value for successful ablation. When both TgD0 and TgD5/TgD0 ratio were considered, that is, TgD05 ng/ml or TgD0or =5 ng/ml but TgD5/TgD0 ratio20, ablation was unsuccessful in only 12/301 patients.Our data show that the TgD5/TgD0 ratio may be used as a new prognostic indicator of (131)I treatment efficacy in patients with DTC.

Thirty-eight patients (25 women, 13 men; mean age, 57.8 [32 to 91]) showing one or more medullary thyroid microcarcinomas (ie, < 1 cm), with no prior MEN II or medullary thyroid carcinoma history in their family, were reviewed. Follow-up was available for 29 patients (mean, 53.6 months [1 to 147]). 21 patients (72.4%) are alive and free of disease, four patients (13.8%) died during follow-up without disease, 2 patients are alive with disease (local recurrence and persistent hypercalcitoninemia) after 80 and 99 months, respectively, and 2 patients died of disease after 24 and 46 months. Most tumors were incidental pathological findings (19 of 38) or were discovered by systematic blood calcitonin measurement for a nodular thyroid disease (15 of 38). Only the four patients who had an unfavorable outcome were symptomatic cases (palpable micro-MTC, diarrhea, cervical lymph node metastasis and pulmonary metastatic disease). The two patients with metastatic disease at diagnosis died during follow-up. In univariate analysis, a symptomatic medullary thyroid carcinoma was a strong predictor of an unfavourable outcome (p < .00008), as were the preoperative calcitonin level (P = .007) and an elevated postoperative calcitonin level (P = .004). Among 30 histopathological criteria, only the presence of amyloid correlated with an unfavorable outcome (P = .018).

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.

Background Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management. Objective To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis. Design and patients Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database. Measurements Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis. Results Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure was solely dependent on stage. Conclusion Survival of these medullary thyroid carcinoma patients appears better than expected even in non-cured patients. Considering the strong impact of stage, the necessity for pre-operative diagnosis of MTC is obvious.

The aim of our study was to assess the ability of routine calcitonin (CT) measurement to improve the preoperative diagnosis of medullary thyroid carcinoma (MTC) in nodular thyroid diseases. We systematically determined basal CT in 1167 patients before thyroid surgery and performed a pentagastrin (Pg) CT stimulation test in 121 of these patients whose basal CT level was normal. Sixteen MTC (1.37%) were found on histopathological examination of surgical specimens: 14 in the 34 patients (41.1%) with abnormal basal CT levels and 2 in the 1133 patients with normal basal CT levels (0.17%). An abnormal increase in Pg-stimulated CT was observed in 7 of the 121 patients tested and was related to microscopic MTC in 2 cases. Among 1167 thyroidectomized patients with nodular thyroid diseases, the prevalence of MTC was 1.37% and reached 41.1% when the basal CT level was abnormal (3% of the patients). CT evaluation detected MTC, whereas other procedures, such as fine needle aspiration cytology, failed, thus allowing early radical surgery. CT measurement should thus become a routine part of the diagnostic evaluation of nodular thyroid diseases.

A new calcitonin (CT) immunoradiometric assay, using anti-11-7 and anti-24-32 CT fragment monoclonal antibodies was evaluated and compared to classical RIA. The sensitivity was 2.5 ng/L, the normal basal level (n = 83) was lower than 10 ng/L, the response to pentagastrin stimulation in control subjects was absent in nine and between 10-30 ng/L in nine others. (mean, 15.4). In patients with renal failure the basal level was increased between 10-52 ng/L. In patients with medullary thyroid carcinoma (MTC; n = 28), the basal level was between 189-28,900 ng/L. A pentagastrin test was performed as screening for familial MTC in eight patients with confirmed MTC at subsequent surgery; the calcitonin peak was equal or greater than 38 ng/L. Large differences exist between CT levels measured by RIA and immunoradiometric assay. The latter method provides a greater sensitivity to pentagastrin test and allows a better identification of microcarcinoma in hereditary cases of MTC.

We recently reported that renin, angiotensinogen, and angiotensin-converting enzyme were present in normal human pituitary lactotroph cells and PRL-secreting adenomas. Angiotensin-II and -III have also been shown to modulate PRL release in vitro. The present study was designed to determine whether angiotensin modulates PRL secretion in vivo. In 36 hypertensive patients with widely varying renin levels, active renin and basal PRL levels did not correlate. In 10 normal volunteers, both a sustained infusion of angiotensin-II and a graded infusion of angiotensin-III induced a 2- to 3-fold increase in aldosterone levels, but had no effect on PRL secretion. Administration of the angiotensin-converting enzyme inhibitor captopril had no effect on PRL circadian rhythm in 10 normal subjects or on PRL concentrations in 11 patients with PRL-secreting adenomas. Cross-over administration of placebo and captopril did not affect the peak PRL level measured after TRH treatment in 10 hypertensive men (placebo, 43.1 +/- 5.4; captopril, 40.0 +/- 6.2 micrograms/L; P = NS) or the rise in PRL induced by doperidone in 6 normal women (placebo, 129.5 +/- 16.2; captopril, 150.0 +/- 35.7 micrograms/L; P = NS). Further, administration of enalapril for 30 days to 6 hypertensive patients did not alter basal PRL concentrations or the peak concentrations induced by TRH. These data indicate that in humans the circulating renin-angiotensin system does not interact with diurnal PRL release or with the response to TRH or domperidone.

The association of haemochromatosis and bone disease is well established, but osteoporotic fracture is an unusual presentation of the disease. We describe a male patient with osteoporotic fractures as a presenting feature of haemochromatosis. The bone histomorphometry showed a dramatic decrease in trabecular bone volume associated with a decrease in cortical bone thickness. Osteoblastic and osteoclastic activities were reduced without any sign of osteomalacia. Staining for iron with Perl's stain showed focal localization at the interface between mineralized trabecular bone and bone marrow. This observation leads us to review the possible mechanisms of osteoporosis.

Serum Tg (sTg) assays are sometimes unsatisfactory for monitoring thyroid cancer because interference caused by anti-Tg antibodies may reduce the sensitivity of the tests during thyroid hormone therapy. We have therefore developed a complementary method using real-time quantitative RT-PCR based on the amplification of Tg mRNA. Two different pairs of primers were used for the determination of the frequency of one of the variants of the alternative splicing of Tg mRNA. The frequency of this variant was as high in patients (n = 40) as in controls (n = 30), accounting for about 33% of the total Tg mRNA. Using appropriate primers, we observed that Tg mRNA values in controls varied according to the volume of thyroid tissue and the TSH concentration. The Tg mRNA values allowed the definition of a positive cutoff point at 1 pg/microg total RNA. This cutoff point, tested on the group of patients treated for thyroid cancer, produced fewer false negative results than those obtained with sTg assays. The standardized, highly sensitive real-time RT-PCR technique may therefore prove useful as a complement to sTg assays, particularly for patients with recurrent thyroid cancer receiving T(4) therapy.

AIMS--To examine the possible consequences of high plasma concentrations of bromine on thyroid hormone. METHODS--Bromine was measured by inductively coupled plasma mass spectrometry in the plasma of 799 patients consulting for thyroid disorders. Because the mean (SD) bromine concentration in the plasma of healthy subjects is 4 (1) mg/l, concentrations above 6 mg/l were regarded as outside the normal range. Bromine, free thyroxine (FT4), and thyroid stimulating hormone (TSH) values were compared. RESULTS--The percentage of patients with normal, low, and high FT4 and TSH plasma activities, measured separately, did not differ between patients with low and high bromine concentrations. The percentage of patients with high TSH but normal FT4 values was significantly higher in the group with bromine values of more than 6 mg/l than in the group with bromine concentrations below this (p < 0.02). CONCLUSION--An increase in plasma bromine could potentiate an increase in plasma TSH concentration, probably as a consequence of a minor inhibitory effect on thyroid activity.

Usually, thyroid carcinoma presents as a cold nodule on radioiodine scintigraphy. High-uptake nodules on iodine thyroid scans are associated with an exceedingly low incidence of malignancy. Only 29 cases of carcinomas appearing as hot or warm nodules have as yet been reported. From 1993 to 1999, we have observed eight similar cases (4 hot and 4 warm thyroid nodules) suggesting that thyroid carcinomas may not be as rare as usually considered in these circumstances. Four tumors were available for molecular analysis on paraffin-embedded sections. Because no mutations were found in the whole coding portions of thyrotropin-receptor (TSH-R) gene and fragments encompassing the mutational hot spots of the G(s alpha) gene, it is unlikely that activating mutations of the TSH-R or G(s alpha) genes were involved in these carcinomas.

A shorter life expectancy, a higher peak bone mass and the absence of distinct menopause equivalent explain the lower incidence of osteoporotic fractures in men. In contrast to women, osteoporosis in younger men is in most cases secondary. Causes such as prolonged glucocorticoid therapy, ethanol abuse, hypogonadism and gastrointestinal disorders are now well recognized. The impact of cigarette smoking, low calcium intake, vitamin D deficiency, hypercalciuria and thyrotoxicosis is more controversial but seems to constitute real risk factors for bone loss. Furthermore increased propensity to fall also plays a major role in fracture risk, particularly in alcoholic patients and in elderly men with neurologic disorders.

Determine a means of establishing the diagnosis of parathyroid cysts preoperatively.Classically, crystal-clear watery fluid removed by fine-needle aspiration of a suspected thyroid mass raises the suspicion of a parathyroid cyst. Immunoradiometric assay of parathyroid hormone level in the fluid may give the diagnosis sparing unnecessary surgery.Over the last 5 years, among the 12 patients presenting a suspected thyroid cyst containing a crystal-clear fluid, we were able to diagnose 3 cases of parathyroid cysts due to the considerable elevation of parathyroid hormone in the puncture fluid. None of these patients had hyperparathyroidism. In patients with a thyroid cyst, parathyroid hormone level in the puncture fluid was nil.The parathyroid nature of cervical cysts containing crystal-clear fluid can be established by assaying parathyroid hormone in the puncture fluid. Non-functional parathyroid cysts may be treated by repeated aspiration. Serum calcium level must be checked regularly to detect potential hyperparathryoidism.

BACKGROUND: Once genetic testing accurately identifies MEN 2 gene carriers, affected children are given the opportunity to undergo thyroidectomy at the earliest stages of the C-cell disease. OBJECTIVE: To define reliable parameters by which to identify the best moment for thyroidectomy in patients who are carriers of the MEN 2 gene. PATIENTS AND METHODS: Seventy-one MEN 2/FMTC gene carriers, collected through the national register of the French Calcitonin Tumours Study Group, were evaluated. All the patients included were younger than 20 years of age and underwent total thyroidectomy. Basal and pentagastrin-stimulated calcitonin were assayed using an immunoradiometric method (sensitivity less than 2pg/ml). Calcitonin measurement was evaluated on the basis of histopathological findings in surgical thyroid specimens. RESULTS: We found C-cell hyperplasia or medullary thyroid carcinoma in all the 71 gene carriers - even for the youngest patients - and nodal metastases were present in four cases. Calcitonin measurement (basal or pentagastrin-stimulated) detected C-cell disease preoperatively in all patients. Six of the 71 patients were not surgically cured: one had nodal metastases, one had an advanced staged disease and four had an incomplete nodal dissection or had not undergone lymph node surgery. CONCLUSIONS: Determination of calcitonin forms an integral part of the management of MEN 2 gene carriers. Thyroidectomy is undisputably indicated when basal calcitonin is abnormal. When basal calcitonin is undetectable, a pentagastrin-stimulated increase in calcitonin to more than 10 pg/ml indicates an early thyroidectomy to cure the patient.

A prospective longitudinal study was conducted to investigate the influence of prolonged suppressive L-thyroxin therapy on bone density and biochemical markers of bone remodeling.Seventy-one patients (including 28 menopaused women) taking long-term L-T4 for thyroid carcinoma were divided into 3 groups according to their TSH level: low (TSH0.04 mlU/l), moderate (0.04 TSHor = 0.10 mlU/l) and high (TSH0.10 mlU/l). Bone density was measured in lumbar vertebrae annually for a mean 4.5 years. Bone metabolism markers were measured over a 4 year period. Bone density measurements of the femur were also obtained for 2 years in 16 menopaused women.Lumbar bone density did not decline whatever the TSH level or the duration of L-T4 treatment. Likewise for menopaused women without substitution estroprogesterone therapy. Over the 4 years, biochemical markers of bone formation, including bone alkaline phosphatases and osteocalcin, or of bone resorption, including urinary hydroxyprolin, did not vary. In addition, in menopaused women, femoral bone density was not significantly lowered over the 2 years follow-up. No lumbar or femoral osteopenia was observed in these patients taking L-thyroxin, even for those with complete TSH blockade. Biochemical markers did not demonstrate a significant acceleration of bone turnover during prolonged administration of L-T4 at suppressive levels.

Calcitonin (CT) assay is essential for recognizing medullary thyroid carcinoma (MTC), particularly occult familial MTC. In previous radioimmunoassays of calcitonin, polyclonal antibodies were used. Here we evaluate a new two-site immunoradiometric assay (IRMA) of calcitonin based on use of monoclonal antibodies. We assayed samples from healthy subjects, patients with renal failure, and subjects from families affected by MTC. Basal values for healthy subjects were all less than 10 ng/L. Renal failure is associated with increased basal CT. The CT peak under pentagastrin stimulation in healthy patients was less than 30 ng/L. In familial screening, basal values greater than 10 ng/L or peak values greater than 30 ng/L correspond to subjects with histologically confirmed MCT or micro-MCT. Polyclonal RIA performed in the same subjects failed to detect the moderate increase of CT that IRMA demonstrated. Preliminary results indicate that this new method may allow earlier detection of CT increase and thus improved diagnosis of MCT, particularly in familial screening. Monitoring surgical patients could also be improved by this new assay.

Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management.To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis.Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database.Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis.Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure was solely dependent on stage.Survival of these medullary thyroid carcinoma patients appears better than expected even in non-cured patients. Considering the strong impact of stage, the necessity for pre-operative diagnosis of MTC is obvious.

Nodular thyroid disease, indicated by the presence of single or multiple nodules within the thyroid gland is a common clinical problem, the main question remains the malignancy. Radionuclide scanning, ultrasonography and fine needle aspiration biopsy have been helpful to distinguish benign from malignant nodules and to select patients for surgery.We performed a prospective study to assess the comparative value of fine needle nonaspiration biopsy and thyroid scinti scan in the management of 412 patients operated for solitary thyroid nodule.Sensitivity and negative predictive values were the same for both methods, but specificity of cytology was greater than that of thyroid scinti scan (80.53% vs. 10.47%, p0.001).Thyroid radionuclide scanning remains valuable in the evaluation of a cytological benign solitary thyroid nodule when TSH value is low, in order to distinguish toxic adenoma from cold nodule in Graves' disease.

In the multiple endocrine neoplasia (MEN) type 2A and in the familial medullary thyroid carcinoma (FMTC), the recent development of genetic testing has provided new methods of identifying disease gene carriers. The use of sensitive immunoradiometric calcitonin (CT) assays led us to evaluate reference ranges of plasma CT responses after pentagastrin in healthy subjects in order to discuss the place of pentagastrin testing in the management of hereditary MTC. Basal and pentagastrin-stimulated CT concentrations were measured in 71 healthy volunteers--aged 20-67 years--and 76 genetically unaffected members of families with hereditary MTC--aged 4-61 years. In healthy subjects, CT peak values were below 30 ng/l in 68 cases and below 50 ng/l in 3 cases. In the genetically unaffected patients, CT peak values were below 15 ng/l in young patients and below 30 ng/l in patients older than 19 year excepted 5 men with stimulated CT levels ranging from 36.5 to 52 ng/l. In 2 of these 5, thyroidectomy revealed C-cell hyperplasia. Borderline test results are not sufficient to establish diagnosis of MTC and in these familial syndromes, management has to be based on the results of genetic testing. However, the determination of the upper normal limit for stimulated CT concentrations in young patients (15 ng/l) may help to identify the optimal moment for surgery.

Serum calcitonin (CT) assays are the most useful tumoral marker for the diagnosis and follow up of medullary thyroid carcinoma (MTC). Since 1988 the sensitivity and specificity of CT assays have been considerably improved. Normal basal and pentagastrin (Pg) stimulated CT ranges remain to be established and it appears necessary to determine the pathological circumstances which may be responsible for hypercalcitoninemia in addition to MCT. By reviewing literature and data from the "Groupe d'Etude des Tumeurs à Calcitonine": a/we compared basal and Pg stimulated CT values obtained with two commercially available immunometric CT assays and we observed that CT values measured by the CT-EASIA MEDGE-NIX kit were three fold the values obtained by suing the hGH ELSA CIS BIOINDUSTRIE Kit; b/we determined that hypercalcitoninemia may be observed in isolated C Cell Hyperplasia (HCC) surrounding either lymphocytic thyroiditis or follicular thyroid carcinoma loci, in chronic renal failure on maintenance hemodialysis, and in various neuroendocrine tumors. Surprisingly, the hypercalcitoninemia related to HCC has been found in genetically unaffected members (without any identified gene RET mutation) of both a Multiple Endocrine Neoplasia type 2A and isolated familial hereditary MTC.

The diagnosis of pseudohypoparathyroidism with osteitis fibrosa was made in a 51-year-old woman on the basis of hypocalcaemia, elevated plasma PTH (1–84) and blunted cAMP response to hPTH infusion. Radiologically, widespread signs of hyperparathyroidism were observed and quantitative histomorphometry confirmed the increased bone cellular turnover. Treatment with calcitriol (1,25 dihydroxyvitamin D3) induced a dramatic improvement of bone lesions. During treatment PTH (1–84) normalized with high dosage of calcitriol in spite of low or subnormal levels of serum calcium, and subsequently increased for each reduction of calcitriol dosage despite normal calcium levels. Our observations support a major and direct effect of 1,25 dihydroxyvitamin D3 on the regulation of parathyroid secretion of parathyroids glands.

Amiodarone is a widely-used anti-arythmic drug that induces an iodine overload and, in 1 to 23% of the patients, a thyrotoxicosis. In a few cases, the thyrotoxicosis may be refractory to conventional pharmacological therapy, thus leading to thyroidectomy. We report the thyroid gland pathology in 5 thyroidectomies that were performed for uncontrolled thyrotoxicosis, induced by amiodarone (4 cases) and by Colchimax, another iodine-rich drug (1 case). Two cases have been studied by electron microscopy. Pathologic findings were: [1] colloid transformation of the parenchyma, [2] areas of follicular disruption with numerous foamy macrophages in the colloid, [3] regenerative areas and [4] a moderate T lymphocytic infiltration. No lysosomal lamellar inclusion body was found by electron microscopy. These lesions may be rather specific of an iodine toxicity. The pathogeny is still misunderstood, and probably complex. It may essentially involve toxic mechanisms, as well as immunologic or allergic mechanisms.

We first compared the analytical performances in terms of precision of two different generation thyrotropin (TSH) assays: Amerlite TSH-60 Assay (K2-TSH) versus Berilux hTSH (B3-TSH) and Kodak Amerlite TSH-30 Ultrasensitive Assay (K3-TSH). Then, we compared the clinical performances in 69 thyrotropin-suppressed patients with thyroid cancer and in 17 other patients referred for newly diagnosed hyperthyroidism. All the patients were given 200 micrograms of Protirelin IV for TRH testing. At the analytical level, the functional detection limit (FDL) was 0.006, 0.017, and 0.04 mU/l for B3-, K3-, and K2-TSH, respectively. At the clinical level of the 17 hyperthyroid patients, 52.9% displayed a positive TRH test with B3, 5.9% with K3, and 11.8% with K2; besides, 29.4% had a basal TSH detectable value with B3, 5.9% with K3, and 11.8% with K2. Among the patients receiving suppressive therapy: 1) 95.6%, 49.3%, and 50.7% showed a detectable TSH response to TRH, with B3-TSH, K2-TSH, and K3-TSH, respectively, and 2) only 5.8% had undetectable basal TSH values with Berilux hTSH, versus 84% with K2 and 89.8% with K3. Considering our findings, we first conclude that third generation TSH assays (having a functional sensitivity limit between 0.01 and 0.02 mU/l) can be useful for monitoring patients on thyroxine suppressive therapy, so as to distinguish partial from more complete thyrotropin suppression. Secondly, even though K3 has a FDL consistent with a third generation TSH assay, it appears less clinically sensitive than B3. Yet, no current assay can thoroughly ascertain a state of overtreatment. Finally, it is important to routinely determine the FDL, which can vary from one kit to the other, within one generation of TSH assays. Indeed, B3 with a FDL at 0.006 mU/l is more useful for monitoring LT4-suppressed patients for thyroid cancer than K3 whose FDL is 0.017 mU/l.

Since the first description by Wolfe et al of C-cell hyperplasia (CCH) in asymptomatic relatives of patients suffering from a medullary thyroid carcinoma (MTC), several investigators have described CCH associated with a chronic lymphocytic thyroiditis (CLT) not within the context of MTC or multiple endocrine neoplasia (MEN). We report the study of C-cell density in 112 cases of CLT on retrospective surgical material to determine the frequency of the association between CCH and CLT. The cases of CLT were compared with 19 normal thyroid glands obtained at necropsy. C cells, immunoreactive with a polyclonal anti-calcitonin (CT) antibody, were counted at high magnification (×400) and the number of low-power magnification (×100) microscopic fields (LPFs) containing at least 50 C cells per slide was assessed. Image analysis was performed to determine the C-cell density expressed in number of C cells/cm 2 . C-cell hyperplasia was defined by the following criteria: C-cell density > 40 cells/cm 2 and the presence of at least three LPFs containing more than 50 C cells. Twenty percent of the cases of CLT showed a CCH thus defined, and four of them had an elevated serum CT level. Statistical analysis showed no clinical or biological correlation with the presence of CCH. However, the frequency of CCH was higher if a follicular cell carcinoma was associated with CLT. This study confirms a pathological association between CCH and CLT, provides new criteria for the definition of CCH on surgical pathology material, and reports four cases with an elevated serum CT level not within the context of MTC or MEN.

A pentagastrin stimulation test using a calcitonin (CT) immunoradiometric assay was performed in 38 healthy subjects and in the following 50 patients: 25 subjects from families with at least 2 known cases of medullary thyroid carcinoma (MTC), 11 subjects from families with apparently sporadic MTC, 2 pheochromocytoma carriers, 1 primary hyperparathyroidism, 8 patients with thyroid nodules, and 3 others with various diseases. In healthy volunteers, basal CT values were always less than 10 ng/L; the response to pentagastrin was below 30 ng/L for 36, and for the remaining 2, the peaks reached 30 for 1 subject and 48 ng/L for the other. The pentagastrin-stimulated CT peak was above 30 ng/L in each of the patients presented here, and all were thyroidectomized. In screening the 25 relatives of patients with familial MTC, a CT peak level over 30 ng/L was constantly associated with C-cell disease (23 cases of MTC and 2 of C-cell hyperplasia). A response to pentagastrin above 100 ng/L was observed in 15 patients among the 23 with MTC. In 8 of the 10 patients with a peak CT level between 30-100 ng/L, pathological examination showed a MTC; the other 2 had C-cell hyperplasia and a negative linkage study analysis. In the 25 other patients in the study without familial MTC, the pentagastrin-stimulated CT level was over 100 ng/L in 11 of the 14 subjects with MTC. The abnormal CT response to pentagastrin, which has been used as a criterion for surgical treatment, is currently determined by an immunoradiometric assay. Our study confirms that subjects with a peak CT level above 100 ng/L should undergo surgery whatever the reason for the test. In the context of inherited MTC, our results suggest that for patients with a CT peak level between 30-100 ng/L, surgery may actually be postponed when their probability of being gene carriers is low. Recent progress with the characterization of specific mutations in affected individuals will make familial screening much easier in the next few months.

Summary OBJECTIVE We report clinical, biochemical, morphological and histological data of phaeochromocytoma in 40 French families and in apparently sporadic cases of multiple endocrine neoplasia (MEN) type 2 A (medullary thyroid carcinoma, phaeochromocytoma, with or without hyperparathyroidism). DESIGN This retrospective study was obtained from cases registered by the‘Groupe d'Etudes des Tumeurs a Calcitonine’ from 1968 to 1990. We analysed the cases having sufficiently precise data on phaeochromocytoma with Pigas Software. PATIENTS Characteristics of phaeochromocytoma In 100 patients with MEN 2 A were reviewed. Phaeochromocytoma was bilateral in 51 %. The disease was inherited in 94 patients from 40 families (40 probands, 54 relatives), and was apparently sporadic In six. RESULTS In this series, diagnostic circumstances were highly suggestive of phaeochromocytoma in 39.8% of the cases, whereas in 43.2%, diagnosis was made through systematic investigations of patients, either before (27.3%) or after (13.6%) thyroidectomy, or after discovery of hyperparathyroidism (2.3%). Fifteen per cent of patients were detected by family screening. Sudden death occurred in 8.9%, malignant phaeochromocytoma In 3%, and ectopic tissue in 4% of the cases. Urinary metanephrines appeared to be the most sensitive screening test. The extent of clinical symptoms was not associated with a particular hormonal pattern. Bilateral adrenalectomy was performed in 60% (in one step in 50%, in two steps in 10%). In these patients, bilateral histological lesions were observed in 92.5%. Simultaneous diagnosis for adrenal and thyroid disease was made in 73.4%, but phaeochromocytoma may be diagnosed before (9.6%) or after (17%) medullary thyroid carcinoma, with an interval greater than 2 years in 25 cases. CONCLUSION Owing to variable clinical symptoms of phaeochromocytoma in these 100 cases of MEN 2 A, systemic biological adrenal assay is required. The search for phaeochromocytoma in medullary thyroid carcinoma (and vice versa) has to be systematically performed, even in apparently sporadic cases. Screening for phaeochromocytoma must be repeated for years, owing to the frequency of bilateral adrenal disease.

AIMS--To examine the advantage of systematic plasma iodine assays in establishing the thyroid function of patients with thyroid disorders. METHODS--Iodine was determined by inductively coupled plasma mass spectrometry (ICPMS) in the plasma of 799 patients consulting for possible thyroid disorders, indicated by FT4 and TSH assays. RESULTS--Plasma iodine was below 40 micrograms/l in 57 (7%) patients, most of whom had hypothyroidism; 40-80 micrograms/l in 439 (55%) patients, most of whom had normal thyroid hormone function; 80-250 micrograms/l in 240 (30%) patients, most of whom had hyperthyroidism; and above 250 micrograms/l in 63 (8%) patients, almost all of whom had iodine overload caused by iodinated drugs, particularly amiodarone, resulting in euthyroidism (24%), hyperthyroidism (36%), and hypothyroidism (16%). Sixty five (7%) had been treated with amiodarone and 27 (3%) with other iodinated drugs. More than 10% of patients with thyroid disorders therefore had an iodine overload. CONCLUSIONS--The determination of total plasma iodine using the simple, accurate ICPMS technique, should be carried out in patients consulting for thyroid disorders, particularly for the detection of an iodine overload.

A 74-year-old man developed bilateral arterial thrombosis of the lower limbs related to heparin-associated thrombocytopenia syndrome (HATS). On day 4 after thrombectomy of both limbs, abdominal pain, fever, hypotension, abdominal tenderness appeared. Acute acalculous cholecystitis was suspected and cholecystectomy was carried out although the gallbladder was not imflamed. Later on, hyponatremia in addition to the aforesaid signs suggested the diagnosis of adrenal insufficiency. Diagnosis was confirmed by low cortisol and aldosterone plasma concentration and by CT scan, which showen two enlarged adrenal glands. HATS might explain two unexpected facts: occurrence of adrenal hemorrhage during heparin therapy with coagulation tests within the therapeutic range and paradoxical thrombosis in the central vein of adrenal gland. HATS must be regarded as one cause of adrenal hemorrhage necrosis.

Serum calcitonin (CT) was determined by radioimmunoassay, using two monoclonal antisera, in 22 women and two men, who had Hashimoto's thyroiditis as confirmed by echographic, immunological or cytological criteria; in 23 patients, serum CT levels were measured after intravenous infusion of pentagastrin (Pg). In 21 cases, basal and Pg stimulated serum CT concentrations were normal. A 61-year-old woman and a 63-year-old man, both euthyroid, had high serum basal CT: 12 pg/ml and 35 pg/ml; infusion of Pg resulted in abnormal increases in serum CT levels: respectively 64 pg/ml and 115 pg/ml. Another patient, a 65-year-old woman with primary hypothyroidism had high serum basal CT: 90 pg/ml (the Pg stimulation test was not done because of ischemic heart disease). Each of these 3 patients had a total thyroidectomy. Pathological examination of the thyroid showed typical features of Hashimoto's thyroiditis and extensive C-cell hyperplasia. After surgery, serum CT levels fell to normal. Therefore, a high serum CT can be observed as the consequence of C-cell hyperplasia in Hashimoto's thyroiditis.

A genetic male with 17 alpha-hydroxylase deficiency is described. The patient, raised as a female, was seen at 17 yr of age for impuberism. She presented all the features of the classical severe form of the disease: complete female phenotype; hypertension; hypokalemia; elevated levels of plasma progesterone, 11-deoxycorticosterone, corticosterone (B), and ACTH; and suppression of renin and aldosterone production. Levels of 17-hydroxyprogesterone, 17-hydroxypregnenolone, and all androgens were barely detectable. Hormone steroid patterns were determined in basal conditions and after acute ACTH stimulation in the parents and the two unaffected brothers in order to identify the heterozygotes. Subtle abnormalities in B and aldosterone secretion were observed in the male members of the family. On the basis of an increased ratio of B to aldosterone the two brothers were assumed to be heterozygotes. The mother had normal basal and stimulated levels of B, deoxycorticosterone, and aldosterone. In the parents and two brothers the progesterone responses to ACTH were exaggerated. The most striking finding in the father and both brothers was the observation of increased basal plasma 17-hydroxyprogesterone, unresponsive to ACTH stimulation, suggesting a partial Leydig cell 17,20-lyase deficiency in the male heterozygotes of this family. This study shows that a short ACTH test can help to identify the heterozygotes in affected families, but the abnormalities found are more heterogeneous than previously suggested.

Highly sensitive TSH assays make it easier to diagnose thyroid diseases. During one year, we performed 5,300 sensitive TSH assays (normal range: 0.15-4 mU/l) in various patients. The purpose of this work was to test the value of the low TSH plasma concentrations found in 580 patients. In 99.7 percent of the cases, low TSH levels were the consequence of a thyroid disorder or a treatment by thyroid hormones; non thyroidal illnesses were detected in only 0.3 percent. However, not all TSH values below 0.15 mU/l were associated with overt or occult thyrotoxicosis. When TSH was undetectable (less than 0.04 mU/l), and excluding thyroid hormone-treated patients, thyrotoxicosis was present in 97 percent of the cases. On the other hand, when TSH values were between 0.04 and 0.15 mU/l, 41 percent of the patients failed to show any sign or symptom of hyperthyroidism, although they had functioning thyroid nodules, multinodular goitre or iodine overload, or they received thyroid hormones.

Renin, angiotensinogen, and converting enzyme were detected in 10 normal human pituitary glands by immunohistochemical techniques. Renin was stained by polyclonal and monoclonal antibodies directed against human renin, and an antibody directed against the renin prosegment revealed the presence of prorenin. Immunoreactive angiotensinogen and angiotensin I-converting enzyme were found in the same cells as renin. Using serial sections and double immunohistochemical labeling with a PRL antiserum, all of the proteins of the renin-angiotensin system appeared to be localized within the lactotroph cells, and no component of the renin system was detected in any of the other pituitary cells. Renin, angiotensinogen, and angiotensin I-converting enzyme also were found in 6 PRL-secreting adenomas as well as in a mixed PRL/GH-secreting adenoma. The renin content of a PRL adenoma was about 1/100th that of a normal kidney. Renin activity could be blocked by an anticatalytic human renin antibody. No renin, angioten-sinogen, or angiotensin I-converting enzyme was found in 6 GH-secreting adenomas, 1 corticotroph adenoma, or 10 nonsecreting pituitary adenomas. The colocalization of proteins of the renin-angiotensin system suggests production of angiotensin II within the lactotroph cells and favors the hypothesis of a paracrine action of this peptide.

Angiotensin-I-converting enzyme (ACE) was detected in 18 germinomas, both of testicular or extratesticular localization, and studied by immunohistochemical methods using specific polyclonal antibodies and by enzyme activity measurements. ACE was also detected in normal human germ cells. On the other hand, it was not present in other types of testicular tumors. Biochemical studies and immunohistochemical findings suggest that at least part of the enzyme is membrane bound. Plasma ACE levels appeared to be normal, indicating that measurement of plasma ACE levels in germinomas would be of little help for the diagnosis and follow-up of patients. However, the apparent specificity of ACE detection in germinomas among germ cell tumors might help in histologic diagnosis, especially for tumors of extragonadal localization.

As Yen admits, polycystic ovarian disease (POD) probably has several causes, one of which involves an adrenal origin. In 20 out of a group of 45 hirsute women, the authors detected a biologic pattern suggesting ovarian dystrophy. Kinetic investigation of the adrenal function in these subjects during a synacthen retard test detected abnormal adrenal hormone production due to partial enzymatic block: in 3 cases of 21-hydroxylase, in 1 case of 11-hydroxylase and in 3 cases of 3 beta-hydroxydehydrogenase. The existence of the first two types of blockade is well established, but that of the third type remains subject to doubt. Systematic screening for disorders of this type during ovarian dystrophy would appear to be of clinical interest. The frequently empirical prescription of dexamethasone in dysovulation in POD cases may find its justification in this phenomenon; the same is also true for the use of bromocriptine in 3 beta-hydroxydehydrogenase.

Renin, prorenin and cathepsin B were localized in human lactotrophs using immunoelectron microscopic techniques. Renin and prorenin were found in numerous cytoplasmic granules. Cathepsin B, a lysosomal enzyme known to be able to activate prorenin into renin, was also present in cytoplasmic granules of lactotrophs. The co-localization of renin and prolactin in the same secretory granules was demonstrated by double immunolabelling. Renin and cathepsin B were co-localized in some granules by the same technique. These results suggest a local activation of renin in the secretory granules of lactotrophs and support the hypothesis of a possible autocrine action of the renin-angiotensin system on prolactin release.

High levels of angiotensin I–converting enzyme (ACE) were found by both direct radioimmunoassay and enzyme activity evaluation in a patient’s plasma that had suprasellar germinoma. ACE levels returned to normal values after surgery, suggesting the tumor was the cause of the elevated plasma ACE. ACE was found in the tumor, and ACE activity was measured in a tumor extract. With the use of specific antihuman ACE antibodies, ACE was localized by immunohistochemistry in the tumoral germinal cells. Because ACE was also found in testicular germinomas, it appears to be a possible marker for germ cell tumors.

Authors report on the case of one patient exhibiting, since three months, a spontaneous thinorrhea and directed to them with the diagnosis of pituitary tumor. The neuro-roentgenologic inquiry discovers a ventricular dilatation and an evagination of the III rd. ventricle into the pituitary fossa ; it also puts in evidence a tumor of the posterior cerebral fossa. We are dealing here with a meningioma of the posterior aspect of temporal pyramid (petrosal bone). If tumoral hydrocephalus is common, its complication with a spontaneous rhinorrhea is, on the contrary, exceptional. We are therefore obliged to consider the pre-existing in this female patient of a deficiency of the pituitary diaphragm that has favoured the intra-sellar diverticle of the III rd ventricle, in the same manner as it makes possible, in other circumstances the arachnoidocele in the syndrome of empty pituitary fossa. Exeresis of the tumor, by suppressing the intracranial hypertension, stopped the rhinorrhea and has considerably improved the visual signs.

Bromocriptine inhibits prolactin release. An increasing number of observations, including the one reported in this paper, provide evidence that bromocriptine can also cause significant reduction in the size of prolactin-secreting adenomas. This effect can now be easily demonstrated by CT scanning. Bromocriptine can be used, not only after surgery has failed, but also in order to facilitate the surgical procedure, thereby increasing the surgical success rate. Some authors suggest that prolactin-secreting adenomas be treated with bromocriptine only. Several questions remain open, for instance, why the response to bromocriptine is unpredictable, and whether prolonged therapy with a dopaminergic drug whose effect is not restrained to hypophyseal cells will have adverse side-effects.