[New immunomodulators in treatment of Graves'ophtalmopathy]. / Les nouveaux immunomodulateurs dans le traitement de l'ophtalmopathie basedowienne.

Treatment of severe Graves'ophtalmopathy (GO) is a complex therapeutic challenge and spite any efforts, about one third of patients are disappointed with the outcome of treatment. Intravenous glucocorticoids (GCIV), orbital radiotherapy, or the combination of both are most frequently used for their immunosuppressive effects. The anti-CD 20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophtalmopathy (TAO). A preliminary study in nine patients with TAO treated with RTX and twenty patients treated with GCIV was reported by Salvi and al. All patients attained peripheral B-cell depletion after the first RTX infusion. At the end of follow-up, clinical activity score values decreased more significantly compared with GCIV. Proptosis and the degree of inflammation decrease significantly in response to RTX. Relapse of active TAO are not observed in patients treated with RTX but occurred in 10 % of those treated with GCIV. If these results are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.

[Thyroid hormone analogs: an important biological supply and new therapeutic possibilities]. / Les analogues des hormones thyroïdiennes : un apport biologique important et de nouvelles possibilités thérapeutiques.

Thyroid hormones [predominantly 3, 5, 3 -I- iodothyronine (T3)] regulate cholesterol and lipoprotein metabolism but cardiac effects restrict their use as hypolipidemic drugs. New molecules have been developped which target specifically the thyroid hormone receptor ss, predominant isoform in liver. The first thyroid hormone agonist, called GC1, has selective actions compared to T3. In animals, GC1 reduced serum cholesterol and serum triglycerides, probably by stimulation important steps in reverse cholesterol transport. Other selective thyromimetic, KB- 2115 and KB - 141 have similar effects. Another class of thyroid hormone analogs, the thyronamines have emerged recently but the basic biology of this new class of endogenous thyroid hormone remains to better understood. Therefore, these molecules may be a potentially treatment for obesity and reduction cholesterol, triglycerides and lipoprotein (a). To date the studies in human are preliminary. Tolerance and efficacy of these drugs are still under investigation.

[Long-term outcome of the adult onset craniopharyngiomas]. / Devenir à long-terme des craniopharyngiomes de l'adulte.

There is few published series dealing on the long-term outcome of the adult-onset craniopharyngiomas. We report the long term clinical, tomodensitometric and MRI data outcome of 35 (23 woman and 12 men) consecutive adult-onset cured for craniopharyngiomas between 1983 and 2002, and followed-up in Rennes University Hospital. The operation was performed via frontopterional approach in 59% and transphenoïdal approach in 41% of cases. Their age at the time of diagnosis was 44.7+/-15.1 years (21-74). The average postoperation follow-up was 7.4+/-7.0 years (0.1-19.1). Recurrence of tumour occurred in 8 patients (25.8%) and a tumor progression in 1 case. The delay of recurrence after initial surgery was 4.1+/-1.3 years (1.4-6.3). Two patients had 5 and 6 years treatment by growth hormone (GH), without tumor recurrence. The observed increase of weight after the surgical cure of craniopharyngiomas concerned 22 patients (63%). The average weight gain was 17.5+/-14.7 kg (1.5-58). In 7 cases (20%) neuropsychological disorders were noted, of which 2 with lost of professional activity. Three patients died. In conclusion the craniopharyngiomas recurrence is frequent and can appear in very prolonged deadlines after the initial surgery.

HLA and Graves' disease: an association with HLA-DRw3.

HLA-A, -B, and -C antigens were tested by a standard lymphocyte microcytotoxicity technique in 86 Caucasians patients from western France with Graves' disease, and the data were compared with findings in 356 healthy controls. For HLA-DR antigen typing performed by lymphocyte microcytotoxicity testing using a long incubation time, the data were compared to findings in 100 healthy controls. An increase was found in the frequency of HLA-DRw3 [51.16% of patients vs. 20% of controls, corrected P (Pc) < 0.0003; relative risk (rr), 4.19) associated with an increased frequency of HLA-B8 (44.19% of patients vs. 22.47% of controls; Pc < 0.001; rr, 2.73) and HLA-A1 (40.7% of patients vs. 28.93% of controls; Pc < 0.03; rr, 1.71). In contrast, a diminished frequency was found for HLA-B12 (12.79% vs. 31.74%; Pc < 0.01). The antigen combination B8-DRw3 was noted in 37 of the 86 Graves' disease patients compared with 13 of 100 controls (Pc < 0.00003). No association was observed between HLA antigens and the different manifestations of the disease, such as the presence of goiter and/or exophthalmos, or the severity of clinical or biochemical signs. The present findings confirm the reported increase in the frequency of HLA-B8 in patients with Graves' disease. The most striking finding was the prevalence of HLA-DRw3, which, together with recent reports on lymphocyte-defined D locus determinants pointing to an increase frequency of HLA-Dw3, suggests that the gene or genes conferring susceptibility to Graves' disease may be located close to the HLA-D (DR) region of the sixth chromosome.

A prospective study of the relationship between relapse of hyperthyroid Graves' disease after antithyroid drugs and HLA haplotype.

One hundred and eleven unselected patients with hyperthyroidism due to Graves' disease received decreasing doses of carbimazole for 18 months. Clinical examination and hormonal assays (serum T3, T4, free T4 index) were done at 4, 9, and 18 months of treatment. Patients were typed for 35 HLA antigens and were followed for 2 yr after withdrawal of treatment; 39 patients were excluded for various reasons and 72 were retained for study. Of the 72 patients, 37 relapsed and 35 remained in remission; 40 patients were DR3+ (20 relapsed) and 32 were DR3- (17 relapsed). HLA frequency was not significantly different in patients who relapsed and those who remained in remission. Thus, under the conditions of this study, HLA frequency could not be used to predict relapse of hyperthyroidism due to Graves' disease.

Antithyroid drugs and Graves' disease: a prospective randomized evaluation of the efficacy of treatment duration.

A prospective randomized study was performed in patients with hyperthyroid Graves' disease (GD) in order to compare long (18 months) and short term (6 months) antithyroid drug treatment on the remission rate. A therapeutic protocol was offered to all GD patients who had not been treated for this disease previously. All patients studied who followed the protocol were rechecked 2 yr after treatment was withdrawn, or earlier in the case of relapse. Of the patients having undergone long term treatment, 61.8% still were in remission 2 yr after treatment withdrawal, whereas only 41.7% of the patients treated for 6 months were in remission (P less than 0.05). Such findings clearly establish that treatment duration has a direct beneficial incidence on the remission rate. These results were confirmed by the fact that treatment for 18 months resulted in remission in 7 of 15 patients who had previously relapsed after a 6-month course of therapy. This improvement in relation to treatment duration might be due to the immunosuppressive action of carbimazole. No significant difference was observed between relapse and remission groups, regardless of treatment duration, for HLA ABDr, serum T3 and T4, and T3/T4 ratio determined before treatment. Only the thyroid-stimulating antibody levels determined at the time of diagnosis and at the end of treatment were higher in the relapse group, a difference that was relevant only globally, due to value scattering. Furthermore, thyroid-stimulating antibody levels at the end of treatment may indicate remission or, conversely, continuance of the pathological process.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum lysosomal acid hydrolase activities in Graves' disease.

The activities of seven lysosomal enzymes (alpha-D-glucosidase, beta-D-galactosidase, beta-D-glucuronidase, hexosaminidase, alpha-L-fucosidase, alpha-D-mannosidase, acid phosphatases) were studied in the serum of 31 untreated patients with Graves' disease, 30 treated hyperthyroid patients whose clinical abnormalities had disappeared and whose hormones had returned to euthyroid levels, and 34 controls. The hyperthyroid state is characterized by increased serum levels of alpha-D-glucosidase, beta-D-glucuronidase, hexosaminidase and especially of alpha-L-glucosidase and alpha-D-mannosidase. In contrast, neither beta-D-galactosidase nor acid phosphatases serum levels were significantly modified. After antithyroid treatment, the activities of these enzymes returned to normal levels, except for alpha-D-mannosidase. The interpretation of these changes in serum acid hydrolases activities is controversial.

[Induction of ovulation by pulsatile gonadoliberin administration. Indications and limits]. / Induction de l'ovulation par l'administration pulsatile de gonadolibérine. Indications et limites.

With its simplicity, innocuity and efficacy, pulsatile GnRH administration constitutes a considerable advance in ovulation induction techniques. Its purpose is not to replace classic methods like Clomiphene Citrate, gonadotropins or dopaminergic agonists, but to complement them. While the choice of administration route, IV vs SC is still controversial, the efficacy depends mainly on the selection of the patients susceptible of benefiting from this therapy. Low gonadotropic activity hypothalamic amenorrhea remains the best indication for pulsatile GnRH, as substantiated by the results published over the last 10 years. The other anovulation causes, including PCO-S, are more disputable indications, and prospective studies involving homogeneous populations are necessary to assess the true standing of GnRH in such indications.

[Serum thyroid hormones and TSH response to TRH during treatment of Graves' disease by carbimazole (author's transl)]. / Hormones thyroïdiennes plasmatiques et test à la TRH au cours de la maladie de Basedow traitée par le carbimazole.

Serum concentrations of Thyroxine (T4), triiodothyronine (T3) free thyroxine index (F.T.I.) and TSH response to TRH were evaluated in 55 Graves' diseases treated by Carbimazole. There is a good correlation between serum thyroid hormones and clinical state: 83,7% for T4; 79,5% for T3; on the other hand there is a discrepancy between T3 and T4 in many cases and between delta TSH and T4 (47%) or T3 (46%). The decrease of T4 occurs before that of T3: 46,6% normal at the 4th month and 72,5% at the 9th month for T4 against 41% and 50% for T3. At the end of the treatment 96,4% of patients are clinically normal but 20% of them remain with T3 and T4 values above normal.

[Acromegaly due to ectopic GH RH secretion by a bronchial carcinoid tumor: a case report]. / Acromégalie par sécrétion ectopique de GH-RH liée à un carcinoïde bronchique: à propos d'un cas.

Ectopic GH RH is a very uncommon cause of acromegaly (<1% of acromegaly). We report the case of an 41 year-old woman with acromegaly due to a GH-RH-secreting bronchial carcinoid tumor. Elevated serum GH (14 ng/ml) was paradoxically stimulated after glucose loading. Magnetic resonance imaging revealed a normal pituitary gland. The thoracic CT demonstrated a voluminous (8 cm) bronchial tumor visualised with octreotide scintigraphy. Acromegaly due to ectopic GH RH secretion was confirmed by very high plasma immunoreactive GH RH level. After removal of the carcinoid tumor, plasmat GH, IGF1 and GH RH levels were normalised.

[Accidents attributable to carbimazole in the treatment of Basedow's disease]. / Les accidents imputables au carbimazole dans le traitement de la maladie de Basedow.

A series of 365 patients (330 women, 35 men) followed up for 9 years during treatment with 20 to 70 mg/day of carbimazole for an average duration of 18 months (range: 2 months to 6 years) was analyzed to evaluate frequency and type of accidents imputable to this synthetic antithyroid agent. Etiopathogenicity of these incidents is reviewed based on reports in the published literature. The product was extremely well tolerated by 349 patients. Minor side effects (hematologic in 0,8%, cutaneous in 1,4% and digestive in 1,6% of cases) were reported in 14 cases (3,8% of cases) and interruption of carbimazole treatment was necessary in 7 of these patients. Major accidents of favorable outcome (Lyell's syndrome, agranulocytosis) were observed in 2 patients (0,6% of cases). Two hypotheses can be evoked to explain their origin: a toxic cause mainly for the hematologic complication or an immuno-allergic mechanism suggested by the rapid onset of complications after beginning treatment. Carbimazole should not, therefore, be considered as a product lacking risks and the accidents observed strongly suggest the need for biological and particularly strict clinical surveillance of patients treated, the appearance of any sign of infection necessitating immediate full and differential blood counts and discontinuation of all therapy.

[Familial surveys in screening for thyroid cancers with amyloid stroma. Report of a personal survey carried out on 80 members of the same family]. / Les enquêtes familiales pour dépistage du cancer de la thyroïde à stroma amyloïde. Présentation d'une enquête personnelle portant sur 80 membres d'une même famille.

We have recently studied a large family of 80 persons in which 47 were examined. The evaluation included history, blood pressure determination, palpation of the thyroid gland and determination of serum carcino-embryonic antigen (C.E.A.) and calcitonin (C.T.). Two members of the kindred had a proven M.C.T. without pheochromocytoma, hyperparathyroidism or Cushing's disease and two others a probable M.C.T. Four members suffered from intestinal occlusion and death occurred in three of them. Our conclusions are: 1) In this family traced through 4 generations: it appears that M.C.T. is transmitted as an autosomal dominant trait with a high degree of penetrance; 2) Our cases associated with those reported in the literature in the past few years point to the existence of a rare but distinct syndrome characterised by the association of M.C.T. and congenital megacolon with hyperplasia of the myenteric plexus; 3) As far as we know, this is the first indication of C.E.A. coupled with elevated calcitonin among several individuals of the same family. We confirm here the conclusions of previous studies: "C.E.A. is a valuable tumour marker which can be used for the detection of M.C.T., particularly if no calcitonin radio-immuno assay is available.

[Thyroid cancer with amyloid stroma. Results of a familial study]. / Cancer de la thyroïde à stroma amyloïde. Résultats d'une enquête familiale.

We have recently studied a kindred in which there have been 2 proven and 2 probable cases of medullary thyroid carcinoma without pheochromocytoma, hyperparathyroidism or Cushing's disease. Four other members suffered from intestinal occlusion and death occurred in three of them. The family has been traced through 4 generations (80 members) and 47 members could be examined; circulating calcitonin and carcinoembryonic antigen levels were measured. This study leads to two conclusions: 1) Medullary thyroid carcinoma is transmitted as an autosomal dominant trait with a high degree of penetrance. 2) Carcinoembryonic antigen is a valuable tumour marker particularly if no calcitonin radioimmunoassay is avialable for the diagnosis of M.C.T.

[HLA DRW3 and Graves' disease (author's transl)]. / Système HLA et maladie de Basedow: prédominance de l'antigène DRW3.

HLA A, B, C antigens were studied in 86 caucasians with Graves' disease, using the lymphocytotoxicity microtechnique. Results were compared to those obtained in 336 healthy controls. HLA DR antigens were studied by the technique of microlymphocytotoxicity after long incubation and results compared to those of 100 healthy controls. There is an increased incidence of DRW3: 51.6% as compared to 20% in controls with a high degree of statistical significance pc less than 0,0003. There is also an increased incidence of B8: 44,19% in Graves' disease against 22,47% in controls pc less than 0,001. These results agree with the conclusions of two recent studies where the incidence of DW3 analyzed by a lymphocytic mixed culture was greater than incidence of the B8 antigen.

[Paraneoplasic Cushing' syndrome. Neurosecretory granules in a lymph node metastasis in electronic microscopy (author's transl) (proceedings)]. / Syndrome de Cushing paranéoplasique. Granules d'aspect secrétoire au sein d'un ganglion métastasique, en microscopie électronique

The authors relate a case of paraneoplasic Cushing's syndrome by mediastinal tumor, probably of thymic origin. All the clinical and biological signs recall similar cases previously related. An "ACTH-like" substance has been found by biological method in a lymphoide metastasis. The main interest resides in the anatomo-pathological findings and more especially in electronic microscopy. The abundance of the neurosecretory granules is a characteristic feature of the malignant cells observed. These granules appear to the authors identical to those observed in other secretory thymomas and various tumors.

[Anti-TPO antibodies and screening of thyroid dysfunction in type 1 diabetic patients]. / Intérêt du dosage des anticorps anti-TPO pour le dépistage d'une dysthyroïdie chez des patients diabétiques de type 1.

The diagnosis of thyroid dysfunction is often late in type 1 diabetic population. So, the aims of this study were 1) to evaluate the prevalences of thyroperoxydase (TPO) and thyroglobulin (Tg) autoantibodies detected by highly sensitive radioimmunological method in a cohort of 258 adult type 1 diabetic patients without evidence of clinical thyroid disease; 2) to determine whether or not measurement of TPO and/or Tg antibodies can identify subjects at risk of clinical or infraclinical thyroid dysfunction by measuring TSH in the entire group. TPO antibodies were found in 45 of the 258 diabetic patients (17%). The prevalence of TPO antibodies was not influenced by the following factors: gender, duration of disease, age at screening and at diabetes diagnosis, positivity of familial history. Tg antibodies were found in 19 patients (7%), including 13 cases with TPO antibodies. All patients without TPO antibody (n=213), including Tg-positive patients displayed TSH values in normal range. Among the 45 TPO-positive patients, 11 patients displayed infraclinical thyroid dysfunction. At the end of the 5-year follow-up, only 2/45 patients became anti-TPO negative. Thirteen of the 45 patients developed subclinical or clinical thyroid diseases (4 Graves'disease and 9 thyroiditis with hypothyroidism). By contrast, none of 45 TPO negative patients, sex and age matched with the TPO-positive patients, developed during follow-up anti-TPO positivity and/or infraclinical thyroid dysfunction. In conclusion, the determination of TPO antibodies by a highly sensitive method allows identifying diabetic patients with thyroid autoimmunity and at risk of subsequent impaired thyroid function, whatever age at diagnosis and diabetes duration. By contrast, anti-Tg determination did not give further information about subsequent thyroid dysfunction. In TPO antibody positive patients repeated thyroid clinical examination and TSH determination could be recommended to detect infraclinical thyroid dysfunction.

[Pilot study and preliminary validation of the French version of a quality-of-life questionnaire specific for subjects with growth hormone deficiency]. / Etude pilote et validation préliminaire de la version française d'un questionnaire de mesure de la qualité de vie spécifique des sujets atteints de déficit en hormone de croissance.

This study forms part of a research project seeking to develop a standardized questionnaire by which clinicians can assess the impact of growth hormone (GH) deficiency and its treatment on the "perceived health" or health-related quality of life of adults. The specific aim of this study was to translate and adapt for French patients the AGHDA (Adult Growth Hormone Deficiency Assessment) a standardized health-related quality of life measure for use with GH-deficient adults, initially developed in the United Kingdom, and to collect data which could be used to assess the main psychometric characteristics of its French version the ISPA-HC (Indicateur de Santé Perceptuelle Adulte-Hormone de Croissance). The main properties analyzed are: 1/ The scale's acceptability, as determined by means of face-to-face interviews with a small number of subjects, then by an ad hoc questionnaire administered during a test-retest study; 2/ The scale's reliability, as determined by a test-retest study (with a 15-days interval between tests); 3/ The scale's concurrent validity, as expressed by comparison with scores obtained by means of a generic quality of life scale, the ISPN (the French version of the Nottingham Health Profile). The results of this first trial with the ISPA-HC are conforming to what one can expect from a good instrument. The ISPA-HC has been shown to have very good levels of reliability and internal consistency. Its scores show a close correlation with those of the ISPN (the French version of the Nottingham Health Profile). This instrument can be used to measure variations in the perceived health of subjects with growth hormone deficiency. Its responsiveness to change is to be examined in subsequent studies.

[Synthetic antithyroid drugs and Basedow's disease or the choice of a therapeutic strategy]. / Antithyroïdiens de synthèse et maladie de Basedow ou le choix d'une stratégie thérapeutique.

We present the conclusions of two prospective studies of patients examined at their first manifestation of Graves' disease and treated with antithyroid drugs (ATD). The purpose of the first study was to investigate the effects of long-term treatment: the patients were given carbimazole in degressive doses without hormone replacement for 18 months, the followed up for 2 to 6 years after drug withdrawal. The second study was designed to determine the effect of treatment duration on the prognosis: the patients were given an ATD according to the same protocol for a duration randomly set at either 6 or 18 months, then seen again 2 years after ATD withdrawal. The results showed that after 18 months of treatment at least 50 percent of the patients could be expected to remain in remission for 6 years. Remissions were less frequent when treatment was shorter (41.7 percent after the 6 month treatment versus 61.8 percent after the 18 month treatment, with a 2 years' follow-up; P less than 0.05). The relapses that occurred came early: 70 percent of them took place within the first post-treatment month. This article also provides evidence of high T3 and/or T4 levels without signs of thyrotoxicosis during the post-treatment clinical course; these exclusively biochemical relapses spontaneously disappeared and may have been expressing epidoses of active thyroiditis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Relapse in Basedow's disease after treatment with synthetic antithyroid drugs. Prognostic value of analysis of the HLA system]. / Rechutes de maladie de Basedow après traitement par antithyroïdiens de synthèse. Valeur pronostique de la détermination du système HLA.

One hundred and eleven unselected patients with hyperthyroidism due to Graves' disease received decreasing doses of carbimazole for 18 months. Clinical examination and hormonal assays (serum T3, T4, free T4 index) were done at 4, 9 and 18 months of treatment. Patients were typed for 35 HLA antigens and were followed up for 2 years after withdrawal of treatment; 39 patients were excluded for various reasons and 72 were retained for study. Of the 72 patients, 37 relapsed and 35 remained in remission: 40 patients were DR3+ (20 relapsed) and 32 were DR3- (17 relapsed). HLA frequency was not significantly different in patients who relapsed and in those who remained in remission. Thus, under the conditions of this study, HLA frequency could not be used to predict relapse of hyperthyroidism due to Graves' disease. This study brings out an other interesting point: relapse frequency of about 50% focuses our attention on the limits of medical treatment.

[Gastric bypass in the treatment of major obesity. 15 cases]. / Les courts-circuits gastriques dans le traitement de l'obésité majeure. Quinze observations.

Gastro-jejunal bypass, as derived from Mason's technique, consists of excluding most of the stomach, leaving only a 60 ml fundic pouch anastomosed with a Y-shaped jejunal loop. Fifteen patients (11 women and 4 men), aged from 21 to 51 years, were operated upon by this technique. In 3 of them, a jejuno-ileal bypass was transformed into a gastric bypass. The amount of weight lost by each individual patient was unpredictable and varied, in fact, from 1 to 50 kg (mean :30 kg). This was obtained within the 6 months following surgery, after which weight remained stable. All but one of the patients failed to attain their ideal weight. The only post-operative complication observed was abscess of the abdominal wall in 3 cases. Digestive disorders were constant during the first 3 months, but rapidly subsided thereafter. In view of the overall satisfactory loss of weight and low incidence of complications, this treatment can be considered useful. However, it should only be applied after strict selection and provided the patient's nutritional status can be regularly supervised.