[Subclinical hyperthyroidism: from diagnosis to treatment]. / Les hyperthyroïdies subcliniques: du diagnostic a la prise en charge.

Subclinical hyperthyroidism is a common clinical entity. Subclinical hyperthyroidism is defined as a serum TSH below the reference range but a normal T4 and T3 level in an asymptomatic patient. Whether or not subclinical hyperthyroidism should be treated remains a matter of debate. Cross-sectional studies and longitudinal population-based studies demonstrate association between subclinical hyperthyroidism and risk of atrial fibrillation, osteoporosis and cardiovascular and global mortality. However, there are no randomized clinical trials answering the question whether long term-health outcomes are improved by the treatment of subclinical hyperthyroidism. Therefore in the absence of evidence for or against treatment of subclinical hyperthyroidism, it seems appropriate to follow algorithms that consider the level of TSH and the presence of risks factors (age > 65 years, osteoporosis, post menopause and cardiac disease).

[Thyroid dysfunction: interactions between genetic and environmental conditions]. / Le dysfonctionnement thyroïdien: interrelations génétique-environnement.

Thyroid dysfunction (TD) is a very common entity in clinical practice nowadays. Prevalence may be underestimated because of the limitations of epidemiological studies. There are mainly genetic and environmental factors that interact on thyroid function. Genetic factors are extensively described in literature but molecular advance on the field may change older classifications based on B-cell or T-cell mediated disorders. The dominant pattern of inheritance makes family predisposition a relevant question in patient medical history but clinical research show that immune system is not enough to cause overt dysfunction. The role of environmental factors generates debate on medical literature. Some classic factors as iodine intake are well characterized but others as fetal microhimerism or new antineoplastic agents are less known. A review of medical literature on thyroid dysfunction has been performed and genetic and environmental factors are described in this article.

[What is the management for foot ulcers in diabetic patients?]. / Que faire devant un ulcère du pied chez un patient diabétique?

The "diabetic foot" covers the spectrum of neurological, arterial and infectious foot problems that occur as a consequence of diabetes. The wounds, often due to minor injuries, may lead to amputations if not quickly treated. The treatment consists of efficiently alleviating mechanical pressure from the wound (i.e. prevention of repeated trauma by walking on the ulcer) on the one hand, and using adequate local care on the other. In addition, the patient's vascular status needs to be assessed and corrected. If present, infections must be quickly and aggressively treated. The infection may be either superficial or deep and the presence of bone contact at clinical examination is suggestive of osteitis. Optimal care is provided in diabetic foot centers by multidisciplinary teams. These teams include a diabetologist, dermatologist, vascular surgeon, infectiologist, radiologist, podologist, shoemaker and specialized nurses. The main aim is to reduce the number of amputations. The best treatment, however, aims at prevention of foot wounds. It requires knowledge of the physiopathological mechanisms of diabetic foot, the screening for feet at risk, and the education of the patient, family and health care providers.

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice.

Human rearranged RET/PTC3 (papillary thyroid carcinoma) proto-oncogene and high-risk human papillomavirus (HPV) type 16 E7 oncogene induces in the mouse a neoplastic transformation of thyroid follicular cells. We present a detailed immuno-histological study (170 mouse thyroids: RET/PTC3, E7, wild type, 2- to 10-month-old) with cell cycle proliferation and signalling pathway indicators. The characteristics of both models are different. There is an 'oncogene dependent' cellular signature, maintained at all studied ages in the E7 model, less in the RET/PTC3 model. During tumour development a large heterogeneity occurred in the Tg-RET/PTC3 model within a same tumour or within a same thyroid lobe. The Tg-E7 model was less heterogeneous, with a dominant goitrous pattern. The solid tumour already described in the RET/PTC3 models associated with cribriform patterns, suggested 'PTC spindle cell changes' as in humans PTC rather than the equivalent of the solid human PTC. Proliferation and apoptosis in the two thyroid models are related to the causal oncogene rather than reflect a general tumorigenic process. The thyroids of RET/PTC3 mice appeared as a partial and transient model of human PTCs, whereas the Tg-E7 mice do not belong to the usual PTC type.

Roles of hydrogen peroxide in thyroid physiology and disease.

CONTEXT: The long-lived thyroid cell generates, for the synthesis of thyroid hormones, important amounts of H2O2 that are toxic in other cell types. This review analyzes the protection mechanisms of the cell and the pathological consequences of disorders of this system. EVIDENCE ACQUISITION: The literature on H2O2 generation and disposal, thyroid hormone synthesis, and their control in the human thyroid is analyzed. EVIDENCE SYNTHESIS: In humans, H2O2 production by dual-oxidases and consequently thyroid hormone synthesis by thyroperoxidase are controlled by the phospholipase C-Ca2+-diacylglycerol arm of TSH receptor action. H2O2 in various cell types, and presumably in thyroid cells, is a signal, a mitogen, a mutagen, a carcinogen, and a killer. The various protection mechanisms of the thyroid cell against H2O2 are analyzed. They include the separation of the generating enzymes (dual-oxidases), their coupling to thyroperoxidase in a proposed complex, the thyroxisome, and H2O2 degradation systems. CONCLUSIONS: It is proposed that various pathologies can be explained, at least in part, by overproduction and lack of degradation of H2O2 (tumorigenesis, myxedematous cretinism, and thyroiditis) and by failure of the H2O2 generation or its positive control system (congenital hypothyroidism).

11C-methionine PET for the diagnosis and management of recurrent pituitary adenomas.

PURPOSE: The detection of recurrent pituitary adenoma by magnetic resonance imaging (MRI) is rendered uncertain by the tissue remodelling that follows surgery or radiotherapy. We aimed to evaluate the contribution of PET with 11C-methionine (MET-PET) in the detection and management of recurrent pituitary adenoma. METHODS: Thirty-three patients with pituitary adenoma were evaluated postoperatively by MET-PET, either because of biological evidence of active residual tumour or because of MRI demonstration of non-functional adenoma growth. We studied 24 secreting adenomas and nine non-functional adenomas. RESULTS: In 30 patients, MET-PET detected abnormally hypermetabolic tissue. In 14 out of these, MRI did not differentiate between residual tumour and scar formation. In nine of these 14 cases, major therapeutic decisions were undertaken (radiosurgery and surgery). In another group of 16 patients, both MET-PET and MRI detected abnormal tissue. In one case, neither MRI nor MET-PET detected adenomatous tissue. Finally, abnormal tissue was detected in two patients on MRI solely. In these two cases, failure of MET-PET to reveal the adenoma was attributable to concomitant inhibitory therapy. The sensitivity of MET-PET and MRI varied as a function of the tumour type: all non-functional adenomas were localised by both modalities, while MET-PET detected all adrenocorticotropic hormone-secreting adenomas whereas MRI depicted only one of these eight lesions. Fifteen out of 17 patients treated by radiosurgery showed clinical improvement after treatment. CONCLUSION: We suggest that MET-PET is a sensitive technique complementary to MRI for the detection of residual or recurrent pituitary adenomas. It should gain a place in the efficient management of these tumours.

[Subclinical hypothyroidism]. / L'hypothyroïdie subclinique.

Subclinical hypothyroidism is defined as normal serum free thyroxine and tri-iodothyronine concentrations and a slightly eleveted serum thyrotropin (TSH) concentration. Only laboratory results can detect this disorder. The causes of this disease are the same as those of overt hypothyroidism. Most patients with subclinical hypothyroidism should be treated with thyroxine aiming to reduce the patient's serum TSH concentration to normal. Treatment will prevent progression to overt hypothyroidism and in some cases ameliorate non specific symptoms and lipid profile.

The natural history of thyroid autonomy and hot nodules.

Solitary hyperfunctioning thyroid adenomas are benign monoclonal tumors characterized by their capacity to grow and produce thyroxine (T4) and triiodothyronine (T3) autonomously, i.e. in the absence of thyrotropin (TSH). Mutations of the TSH receptor (TSH-R) have been found in the majority of solitary hyperfunctioning thyroid adenomas. On radioisotope scanning they generally appear as hot nodules because they concentrate radioiodide or 99mTc pertechnate, whereas the normal surrounding and contralateral tissue concentrate little isotopes. A toxic adenoma probably evolves gradually from a small autonomously hyperfunctioning adenoma that initially is only slightly more active than the extranodular tissue. This has been referred to as a "warm" nodule or a "compensated" adenoma. The diagnostic criterion for this designation is the persistence of detectable serum TSH maintaining some radioiodine uptake by the extranodular tissue. This "compensated" adenoma persists as long as the autonomous hormone output is not sufficient to suppress thyrotropin, i.e. to cause hyperthyroidism. The rate of development of thyrotoxicosis in patients with hyperfunctioning adenomas who are euthyroid initially is about 4% per year and depends on the size of the adenoma, iodine intake and age of the patient. No clear relationship can be establish between the nature of the TSH receptor mutations and the phenotype of the tumor.

[The endocrinology department]. / Le Service d'Endocrinologie.

The clinical activities of the department of endocrinology encompass the care and treatment of diabetes, thyroid diseases, hypothalamo-pituitary, adrenal, gonadic and parathyroid diseases, obesity, hypercholesterolemia and paraneoplastic endocrine syndromes. These domains are briefly described. The research activities of the department have investigated the regulation of thyroid metabolism in vitro, the intrathyroid H2O2 generating system, the physiopathology of toxic thyroid nodules and the effects of ageing on the thyreotropic function of the normal ageing male. Studies of "jet lag" conditions have shed a new light on hormonal chronophysiology. Other investigations have considered the regulation of ketone body metabolism, the relationship between nutritional status and glucose metabolism, and some aspects of immunodiabetology.

[Management of thyroid nodule]. / Prise en charge du nodule thyroïdien.

Thyroid nodules are often encountered in clinical practice. Although the vast majority are benign lesions, about 5% may actually be cancerous. The main problem raised by a solitary nodule of the thyroid gland is therefore the diagnosis of neoplasia. Several diagnostic techniques have been proposed to distinguish benign nodules from malignant nodules. These techniques vary in reliability. History taking, physical examination, laboratory studies and diagnostic imaging may help the physician to categorise the nodule but only fine-needle aspiration biopsy provide sensitive and specific results in the diagnostic process. The reliability of this technique is largely dependent on the experience of the person performing the biopsy and that of the cytopathologist interpreting it.

Stimulation by iodide of H(2)O(2) generation in thyroid slices from several species.

The regulation of thyroid metabolism by iodide involves numerous inhibitory effects. However, in unstimulated dog thyroid slices, a small inconstant stimulatory effect of iodide on H(2)O(2) generation is observed. The only other stimulatory effect reported with iodide is on [1-(14)C]glucose oxidation, i.e., on the pentose phosphate pathway. Because we have recently demonstrated that the pentose phosphate pathway is controlled by H(2)O(2) generation, we study here the effect of iodide on basal H(2)O(2) generation in thyroid slices from several species. Our data show that in sheep, pig, bovine, and to a lesser extent dog thyroid, iodide had a stimulatory effect on H(2)O(2) generation. In horse and human thyroid, an inconstant effect was observed. We demonstrate in dogs that the stimulatory effect of iodide is greater in thyroids deprived of iodide, raising the possibility that differences in thyroid iodide pool may account, at least in part, for the differences between the different species studied. This represents the first demonstration of an activation by iodide of a specialized thyroid function. In comparison with conditions in which an inhibitory effect of iodide on H(2)O(2) generation is observed, the stimulating effect was observed for lower concentrations and for a shorter incubation time with iodide. Such a dual control of H(2)O(2) generation by iodide has the physiological interest of promoting an efficient oxidation of iodide when the substrate is provided to a deficient gland and of avoiding excessive oxidation of iodide and thus synthesis of thyroid hormones when it is in excess. The activation of H(2)O(2) generation may also explain the well described toxic effect of acute administration of iodide on iodine-depleted thyroids.

Characterization of autonomous thyroid adenoma: metabolism, gene expression, and pathology.

Fifty-one in vivo characterized autonomous single adenomas have been studied for functional parameters in vitro, for gene and protein expression and for pathology, and have been systematically compared to the corresponding extratumoral quiescent tissue. The adenomas were characterized by a high level of iodide trapping that corresponds to a high level of Na+ /iodide symporter gene expression, a high thyroperoxidase mRNA and protein content, and a low H2O2 generation. This explains the iodide metabolism characteristics demonstrated before, ie, the main cause of the "hot" character of the adenomas is their increased iodide transport. The adenomas spontaneously secreted higher amounts of thyroid hormone than the quiescent tissue and in agreement with previous in vivo data, this secretion could be further enhanced by thyrotropin (TSH). Inositol uptake was also increased but there was no spontaneous increase of the generation of inositol phosphates and this metabolism could be further activated by TSH. These positive responses to TSH are in agreement with the properties of TSH-stimulated thyroid cells in vitro and in vivo. They are compatible with the characteristics of mutated TSH receptors whose constitutive activation accounts for the majority of autonomous thyroid adenomas in Europe. The number of cycling cells, as evaluated by MIB-1 immunolabeling was low but increased in comparison with the corresponding quiescent tissue or normal tissue. The cycling cells are observed mainly at the periphery; there was very little apoptosis. Both findings account for the slow growth of these established adenomas. On the other hand, by thyroperoxidase immunohistochemistry, the whole lesion appeared hyperfunctional, which demonstrates a dissociation of mitogenic and functional stimulations. Thyroglobulin, TSH receptor, and E-cadherin mRNA accumulations were not modified in a consistent way, which confirms the near-constitutive expression of the corresponding genes in normal differentiated tissue. On the contrary, early immediate genes expressions (c-myc, NGF1B, egr 1, genes of the fos and jun families) were decreased. This may be explained by the proliferative heterogeneity of the lesion and the previously described short, biphasic expression of these genes when induced by mitogenic agents. All the characteristics of the autonomous adenomas can therefore be explained by the effect of the known activating mutations of genes coding for proteins of the TSH cyclic adenosine monophosphate (cAMP) cascade, all cells being functionally activated while only those at the periphery multiply. The reason of this heterogeneity is unknown.

Autonomy in endemic goiter.

The occurrence of hyperthyroidism in many individuals after introduction of iodine prophylaxis in endemic goiter areas can have dramatic consequences for the affected individuals. It indicates that in such individuals the increase of serum thyroid hormone level in response to iodine supplementation does not exert its normal negative feedback on thyroid activity, ie, that in such individuals some thyroid tissue has become autonomous. In this short review we summarize what is known about the possible mechanisms, cause, diagnosis, and consequences of thyroid autonomy.

[Lipoprotein metabolism]. / Métabolisme des lipoprotéines.

Since lipids are insoluble in water, they are transported in plasma by lipoproteins composed of several classes of lipids (including cholesterol, triglycerides, and phospholipids) and proteins named apolipoproteins. Each class of lipoprotein has a specific function in lipids metabolism. Chylomicrons transport dietary triglycerides and cholesterol from the intestine to peripheral tissues, Very Low Density Lipoproteins (VLDL), are synthetized by the liver to export triglycerides, Low-Density Lipoproteins (LDL) represent a final stage in the catabolism of Very low density lipoproteins and High Density Lipoproteins (HDL) are involved in reverse cholesterol transport. The role of lipoproteins receptors, enzymes, apolipoproteins and transfer proteins is also discussed.

Effect of short-term starvation on gastric emptying in humans: relationship to oral glucose tolerance.

To evaluate the effects of short-term starvation on gastric emptying in normal and obese subjects, the relationship between gastric emptying and oral glucose tolerance, and the mechanisms responsible for the delay in the systemic appearance of oral glucose observed after short-term fasting, we determined the effects of a 4-day fast on 1) gastric emptying and oral glucose tolerance in normal subjects and 2) gastric emptying in obese patients. Gastric emptying of 75 g glucose (320 ml) labeled with 99mTc colloid was measured in 12 healthy volunteers and 11 obese subjects after 12-h and 4-day fasts. In seven other obese subjects, the effect of a 4-day fast on gastric emptying of 320 ml normal saline was quantified. Gastric emptying of glucose was slower after the 4-day than after the overnight fast in both normal (P = 0.02) and obese (P < 0.001) subjects, with no difference between the two groups. In normal subjects, the rate of gastric emptying was related directly to the rise in plasma glucose at 30 min (r = 0.60; P < 0.05) but inversely to the plasma glucose at 180 min (r = -0.64; P < 0.02). In the obese subjects, gastric emptying of saline was not affected by fasting. These observations indicate that 1) gastric emptying of glucose is retarded by a 4-day fast, 2) the changes in gastric emptying reported in obesity may reflect different patterns of prior nutrient intake, and 3) delay in gastric emptying accounts for the slower systemic appearance of glucose after fasting.

Role of the cyclic adenosine 3',5'-monophosphate and the phosphatidylinositol-Ca2+ cascades in mediating the effects of thyrotropin and iodide on hormone synthesis and secretion in human thyroid slices.

There are two major known regulatory pathways in human thyrocytes: the phosphatidylinositol-Ca2+ cascade (PiP2 cascade) and the cAMP cascade. We study here the regulation of the PiP2 cascade by TSH, ATP, NaF, and bradykinin. Our data show that protein iodination and, thus, the synthesis of thyroid hormones in human thyroid is under the control of both the PiP2 cascade and the cAMP cascade. Activation of the PiP2 cascade by TSH (10 mU/mL), NaF, bradykinin, ionomycin, and 12-O-tetradecanoylphorbol-13-acetate stimulates iodide organification. Conversely, activation of the cAMP cascade by forskolin, TSH (0.3 mU/mL), and dibutyryl cAMP inhibits iodide organification. These metabolic effects are correlated to activations and inhibitions of the H2O2-generating system, showing that H2O2 is a limiting factor for protein iodination in these cells. The cascades also regulate in parallel the activity of the pentose phosphate pathway. The effects of various concentrations of TSH on H2O2 generation and [1-14C]glucose oxidation were tested, showing a dual effect with an inhibition of these metabolisms for low concentrations of TSH (that stimulate the cAMP cascade) and an activation for high concentrations of TSH (that stimulate the PiP2 cascade). The control of thyroid secretion differs from that of protein iodination, in that the cAMP cascade greatly enhances secretion, whereas the PiP2 cascade has no effect on basal secretion and even an inhibitory effect on TSH-stimulated secretion (1 mU/mL). We also demonstrate here the presence of an inhibitory effect of iodide on its own organification in human thyroid (Wolff-Chaikoff effect). This effect is probably mediated through an inhibition of the inositol trisphosphate response to TSH and of the H2O2 response to Ca2+.