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Peter Laurberg, Claire Bournaud, Jesper Karmisholt and Jacques Orgiazzi

Graves' disease is a common autoimmune disorder in women in fertile ages. The hyperthyroidism is causedby generation of TSH-receptor activating antibodies. In pregnancy both the antibodies and the antithyroid medication given to the mother pass the placenta and affect the foetal thyroid gland. Thyroid function should be controlled not only in the mother with Graves' hyperthyroidism but also in her foetus.The review includes two cases illustrating some of the problems in managing Graves' disease in pregnancy.

Major threats to optimal foetal thyroid function are inadequate or over aggressive antithyroid drug therapy of the mother. It should be taken into account that antithyroid drugs tend to block the foetal thyroid function more effectively than the maternal thyroid function, and that levothyroxin (l-T4) given to the mother will have only a limited effect in the foetus.

Surgical thyroidectomy of patients with Graves' hyperthyroidism does not lead to immediate remission of the autoimmune abnormality, and the combination thyroidectomy+withdrawal of antithyroid medication+l-T4 replacement of the mother involves a high risk of foetal hyperthyroidism.

Conclusion

Antithyroid drug therapy of pregnant women with Graves' hyperthyroidism should be balanced to control both maternal and foetal thyroid function. Surgical thyroidectomy of a pregnant woman with active disease may lead to isolated foetal hyperthyroidism.

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Nathalie Lévy Bohbot, Jacques Young, Jacques Orgiazzi, Catherine Buffet, Maud François, Brigitte Bernard-Chabert, Céline Lukas-Croisier and Brigitte Delemer

Autoimmune thyroid disease is a common side-effect of interferon-α (IFN-α) treatment of viral hepatitis C. We have described three patients with hepatitis C for whom IFN-α and ribavirin were prescribed and who developed two successive phases of silent thyroiditis followed by hyperthryroidism relapse due to Graves’ disease. These three men had no known history of familial or personal thyroid disease. Destructive thyrotoxicosis appeared 4–6 months after starting IFN-α, followed by Graves’ hyperthyroidism within 8 to11 months. The thyrotropin (TSH) level was normal before IFN-α was started. The diagnosis of destructive thyroiditis was confirmed by anti-TSH receptor antibody (TSHRAb) negativity and the absence of radionuclide (123I or 99Tc) uptake on thyroid scintiscans. Eight to eleven months after starting treatment, TSHRAb positivity and intense scintigraphic uptake confirmed the appearance of Graves’ disease. IFN-α was continued in only one patient. Hence, hyperthyroidism induced by IFN-α could correspond to the first phase of silent thyroiditis, to Graves’ disease or to the succession of both. Rigorous diagnostic procedures with repeated scintiscans and TSHRAb titering are necessary to avoid a false diagnosis and inappropriate therapy.

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Jean-Louis Thomas, Jacques Leclere, Pierre Hartemann, Jean Duheille, Jacques Orgiazzi, Meryl Petersen, Christian Janot and Jean-Claude Guedenet

Abstract.

Thirty-four members of a single family were studied and 9 of them were found to be suffering from hyperthyroidism associated wiht diffuse goitre. Exophthalmos was absent and transmission seemed to be independent of HLA type. Four of the 9 were studied prior to treatment but in all cases serum immunoglobulin levels were normal, antithyroglobulin and antimicrosomal antibodies absent, thyroid stimulating antibodies negative and the lymphocyte transformation responses to mitogens not different from those of controls. The results of testing the euthyroid family members were similarly negative, except in the case of a woman with type I diabetes mellitus who showed a low titre of antimicrosomal antibody.

Seven of the patients underwent subtotal thyroidectomy. Lymphocytic infiltration of the excised portion was rarely present. Four of the glands were subjected to immunofluorescent and electron microscopy but neither immunosecreting cells nor immune complex deposits were found.

These results point to the existence of a non-autoimmune form of goitrous hyperthyroidism, different from Graves' disease.

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Julia Graeppi-Dulac, Virginie Vlaeminck-Guillem, Marie Perier-Muzet, Stéphane Dalle and Jacques Orgiazzi

Bexarotene (Targretin), approved since 1999 as a second-line treatment for late stage cutaneous T-cell lymphomas, has been shown to induce significant hypothyroidism through TSH suppression. This review revisits, through a case report, mechanisms by which rexinoids repress the expression of TSHB gene as well as α TSH and TRH genes. It appears that rexinoids suppress TSH independently from tri-iodothyronine. Bexarotene also differently affects the gene expression of deiodinases 1 and 2 as well as the peripheral clearance of thyroxine. These data might open new ways of research on the potential interaction between thyroid axis and endogenous rexinoids.

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Claudio Marcocci, Torquil Watt, Maria Antonietta Altea, Ase Krogh Rasmussen, Ulla Feldt-Rasmussen, Jacques Orgiazzi, Luigi Bartalena and for the European Group of Graves' Orbitopathy (EUGOGO)

Objective

The objective of this study was to investigate the side effects of glucocorticoid (GC) therapy observed by European thyroidologists during the treatment of Graves' orbitopathy (GO).

Design

A questionnaire-based survey among members of the European Thyroid Association (ETA) who treat GO.

Results

A response was obtained from 128 ETA members of which 115 used GC therapy for GO. The majority of respondents (83/115, 72%) used intravenous (i.v.) GC, with a relatively wide variety of therapeutic regimens. The cumulative dose of methylprednisolone ranged between 0.5 and 12 g (median 4.5 g) for i.v.GC and between 1.0 and 4.9 g (median 2.4 g) for oral GC. Adverse events were often reported during oral GCs (26/32, 81%); most side effects were non-severe, but ten respondents reported severe adverse events (hepatic, cardiovascular, and cerebrovascular complications), including two fatal cases, both receiving a total of 2.3 g prednisone. Adverse events were less common in i.v.GC (32/83 respondents, 39%), but mostly consisted of severe events, including seven fatal cases. All but one fatal event occurred in cumulative i.v.GC doses (>8 g) higher than those currently recommended.

Conclusions

GCs are preferentially administered i.v. for the treatment of GO in Europe. Both oral and i.v.GC may be associated with severe adverse effects, including fatal cases, which are more frequently reported in daily or alternate day i.v.GC. IvGC therapy should be undertaken in centers with appropriate expertise. Patients should be carefully examined for risk factors before treatment and monitored for side effects, which may be asymptomatic, both during and after treatment.

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Juliette Abeillon-du Payrat, Karim Chikh, Nadine Bossard, Patricia Bretones, Pascal Gaucherand, Olivier Claris, Anne Charrié, Véronique Raverot, Jacques Orgiazzi, Françoise Borson-Chazot and Claire Bournaud

Context

Hyperthyroidism occurs in 1% of neonates born to mothers with active or past Graves' disease (GD). Current guidelines for the management of GD during pregnancy were based on studies conducted with first-generation thyroid-binding inhibitory immunoglobulin (TBII) assays.

Objective

This retrospective study was conducted in order to specify the second-generation TBII threshold predictive of fetal and neonatal hyperthyroidism, and to identify other factors that may be helpful in predicting neonatal hyperthyroidism.

Methods

We included 47 neonates born in the Lyon area to 42 mothers harboring measurable levels of TBII during pregnancy. TBII measurements were carried out in all mothers; bioassays were carried out in 20 cases.

Results

Nine neonates were born with hyperthyroidism, including five with severe hyperthyroidism requiring treatment. Three neonates were born with hypothyroidism. All hyperthyroid neonates were born to mothers with TBII levels >5 IU/l in the second trimester (sensitivity, 100% and specificity, 43%). No mother with TSH receptor-stimulating antibodies (TSAb measured by bioassay) below 400% gave birth to a hyperthyroid neonate. Among mothers of hyperthyroid neonates, who required antithyroid drugs during pregnancy, none could stop treatment before delivery. Analysis of TBII evolution showed six unexpected cases of increasing TBII values during pregnancy.

Conclusion

Maternal TBII value over 5 IU/l indicates a risk of neonatal hyperthyroidism. Among these mothers, a TSAb measurement contributes to identify more specifically those who require a close fetal thyroid ultrasound follow-up. These results should be confirmed in a larger series.

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Geneviève Sassolas, Zakia Hafdi-Nejjari, Anne Marie Schott, Claire Bournaud, Jean Louis Peix, Jacques Orgiazzi, Nicole Dutrieux-Berger, Françoise Borson-Chazot and The Group of Pathologists of the Rhône-Alpes Région

Objective

To analyze, at a population level, the relation between the incidences of benign thyroid diseases in patients submitted to surgery and that of thyroid cancers based on their respective geographical distributions.

Methods

The study included 3169 cases (691 cancers and 2478 benign diseases) operated on in 2002 in the Rhône-Alpes région, which is subdivided into eight départements and 311 cantons.

Results

The total thyroid intervention rate was 54.6/100 000 (23.4 and 86.4), and the annual cancer incidence was 11.9/100 000 (4.7 and 13.8) for men and women respectively. The prevalence of cancer among thyroid surgery was 21.8% and that of cancer discovered in goiters increased with age (44% at 60 years). Intervention rates varied from départment to département. In women, the incidence of microcancers was correlated to the thyroid intervention for benign pathologies rate. In men, the incidence of supracentimetric cancers was related to the TIBR. At the canton level, the relative risk of benign diseases was correlated to that of cancers. TIBR and incidence of cancers were higher in urban cantons than in nonurban ones. The density of endocrinologists influenced the prevalence of cancers among all the cases submitted to surgery.

Conclusion

In the Rhône-Alpes population with high rates of thyroid cancer incidence and of thyroid surgery, a number of correlations were found according to gender and tumor size. However, the general incidence of cancer was not directly related to surgical activity. Geographical variability may be related to the heterogeneous medical and pathological practices.

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Geneviève Sassolas, Zakia Hafdi-Nejjari, Laurent Remontet, Nadine Bossard, Aurélien Belot, Nicole Berger-Dutrieux, Myriam Decaussin-Petrucci, Claire Bournaud, Jean Louis Peix, Jacques Orgiazzi, Françoise Borson-Chazot and the Group of Pathologists of the Rhône Alpes Region

Objective

The aim of the present study was to determine recent trends in thyroid cancer incidence rates and to analyze histopathological characteristics and geographical distribution.

Methods

Histologically proven 5367 cases were collected over the period 1998–2006 in France from the Rhône-Alpes thyroid cancer registry. Geographical variations of incidence were analyzed using a mixed Poisson model.

Results

The average incidence rates, age standardized to the world population, were 3.9/100 000 in men and 12.3/100 000 in women, higher than those previously reported in France. After an initial increase during the first 3 years, a steady level of incidence was observed for the period 2001–2006. The annual incidence rate of microcarcinomas was correlated with that of all cancers in men and women (r=0.78 and 0.89; P<0.01) respectively. Papillary microcarcinomas represented 38% of tumors and two-thirds of them measured less than 5 mm in diameter. They were fortuitously discovered after thyroidectomy for benign diseases in 64% of cases. Histological marks of aggressiveness differed according to the size of the tumor. Despite recent advances in diagnosis, 13% of tumors were diagnosed at advanced stage especially in men. Geographical distribution of incidence based on subregional administrative entities showed lower incidence rates in rural than in urban zones in men (relative rate: 0.72; 95% CI: 0.62–0.84) and women (relative rate: 0.85; 95% CI: 0.73–0.93).

Conclusion

The present study suggests that the rise in thyroid cancer incidence is now abating. It could reflect standardization in diagnostic procedures. Further studies, performed on a more prolonged period, are necessary to confirm these data.

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Luigi Bartalena, Lelio Baldeschi, Alison Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Currò, Chantal Daumerie, George J Kahaly, Gerasimos E Krassas, Carol M Lane, John H Lazarus, Michele Marinò, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx and Wilmar M Wiersinga