B Trultzsch, T Nebel and R Paschke
H Gharib, E Papini and R Paschke
In 2006, two major society-sponsored guidelines and one major consensus statement for thyroid diagnosis and management were published by: the American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi (AACE/AME); the American Thyroid Association (ATA); and the European Thyroid Association (ETA). A careful review of these guidelines reveals that despite many similarities, significant differences are also present, likely reflecting differences in practice patterns, interpretation of existing data, and availability of resources in different regions. The methodology of the guidelines is similar, but a few differences in the rating scale make a rapid comparison of the strength of both evidence and recommendations difficult for the use in current clinical practice. Some recommendations are based mostly on experts' opinion. Thus, a same recommendation may be based on a different evidence; on the other hand, sometimes the same evidence may induce a different recommendation. Therefore, efforts are needed to produce a few high-quality clinical studies to close the evidence gaps in the still controversial fields of thyroid disease and to create a joint task force of the most authoritative societies in the field of thyroid disease in order to reach a common document for clinical practice recommendations.
J. TEUBER, R. PASCHKE, R. SCHMEIDL, J. CHRISTOPHEL and U. SCHWEDES
U. SCHWEDES, J. TEUBER, R. PASCHKE and K. H. USADEL
R. PASCHKE, J. TEUBER, U. SCHWEDES and K. H. USADEL
M Fasshauer, J Klein, U Lossner and R Paschke
OBJECTIVE: Galectin-12 has recently been shown to be a predominantly adipocyte-expressed protein which is stimulated by insulin-sensitizing thiazolidinediones and possesses apoptosis-inducing activity. METHODS: To further clarify galectin-12 regulation and its potential involvement in the development of insulin resistance, 3T3-L1 adipocytes were chronically treated with various hormones known to impair insulin sensitivity, and galectin-12 mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Treatment of 3T3-L1 cells for 16 h with 10 micromol/l isoproterenol, 100 nmol/l insulin, 0.6 nmol/l tumor necrosis factor alpha (TNFalpha), and 100 nmol/l dexamethasone reduced galectin-12 gene expression between 47% and 85%. These negative effects were dose-dependent with significant inhibition detectable at concentrations as low as 10 nmol/l isoproterenol, 0.06 nmol/l TNFalpha, and 1 nmol/l dexamethasone. Furthermore, the inhibitory effect of isoproterenol could be almost completely reversed by pretreatment with the beta-adrenergic antagonist propranolol and mimicked by stimulation of G(S)-proteins with cholera toxin or by activation of adenylyl cyclase with forskolin and dibutyryl-cAMP. CONCLUSIONS: Our results suggest that galectin-12 is an adipocyte-expressed protein which is downregulated by various insulin resistance-inducing hormones. These findings imply a role for galectin-12 in the pathogenesis of insulin resistance.
S Miedlich, T Lohmann, U Schneyer, P Lamesch and R Paschke
OBJECTIVE: Familial isolated primary hyperparathyroidism (FIHP) is defined as hereditary primary hyperparathyroidism without the association of other diseases or tumors. Linkage analyses suggest that different genotypes can lead to the same phenotype of primary hyperparathyroidism. Hereditary syndromes associated with primary hyperparathyroidism are multiple endocrine neoplasia type 1 and type 2 (MEN 1 and MEN 2). In MEN 1, multiple parathyroid adenomas occur in more than 90% of the patients. Therefore, it has been suggested that FIHP could represent a variant or partial expression of MEN 1. DESIGN: We report on a large FIHP kindred with a MEN1 gene mutation. Nineteen family members (aged 10 to 87 years) were screened. Furthermore, statistical comparison by Fisher's exact tests of FIHP families with MEN1 gene mutations and MEN 1 families with two or more endocrinopathies was carried out to investigate genotype-phenotype correlations. METHODS: Mutational analysis of leucocyte DNA was carried out by direct sequencing of the complete coding region of the MEN1 gene. Screening of MEN 1 manifestations was carried out by determination of serum calcium, phosphate, parathyroid hormone, prolactin, ACTH, cortisol, IGF-I, gastrin, glucose, insulin, glucagon, serum potassium, aldosterone, plasma renin and urinary hydroxyindoleacetic acid. RESULTS: We detected an in-frame deletion mutation in exon 8 of the MEN1 gene resulting in the deletion of one glutamine acid residue at position 363. It was found in eight individuals. Two of these family members (aged 42 and 60 years) were operated for primary hyperparathyroidism, and three (aged 13 to 40 years) showed mild hypercalcemia and parathyroid hormone levels within the upper normal range or slightly elevated, without any clinical symptoms. Two individuals (aged 12 and 19 years) were normocalcemic. One could not be tested. None of them had clinical evidence of other MEN 1 manifestations. Statistical comparison of the mutation types in families with FIHP and families with two or more MEN 1-associated endocrinopathies reported in other studies reveals a significant difference. In families with FIHP, missense/in-frame mutations have been found in 87.5% of cases whereas in families with tumors in various endocrine glands these mutation types occur much less frequently (21-34%, P<0.05). CONCLUSIONS: These studies indicate that FIHP can represent a partial MEN 1 variant and is often caused by missense/in-frame mutations.
S Miedlich, P Lamesch, A Mueller and R Paschke
OBJECTIVE: Recent studies have shown an influence of the calcium-sensing receptor variant A986S on the serum calcium concentration, suggesting that this genetic variant could be a candidate for various bone and mineral disorders. The intention of this study was therefore to investigate the frequency of the described calcium-sensing receptor variants A986S, R990G and Q1011E in patients with primary hyperparathyroidism to test the hypothesis as to whether these variants represent risk factors for the development of primary hyperparathyroidism. DESIGN: Fifty patients with primary hyperparathyroidism were included in the study. One hundred and two healthy blood donors served as controls. METHODS: Detection of the genetic variants A986S, R990G and Q1011E was done by direct sequencing of exon 7 of the calcium-sensing receptor in leucocyte DNA. RESULTS: The heterozygous variant A986S was found in 34% (17 of 50) of the healthy age- and sex-matched controls and 40% (20 of 50) of the patients with primary hyperparathyroidism. This difference was not statistically significant (P=0.68). However, in male patients the heterozygous variant A986S was found more frequently (67%, 6 of 9) than in male controls (20%, 2 of 10, P=0.07). The variants R990G and Q1011E were found less frequently (8-20%) in patients and controls without significant differences between the groups. Patients with the heterozygous variant Q1011E had significantly higher serum calcium and parathyroid hormone levels than patients with the wild-type variant (P<0.01). There was no correlation of serum calcium (total and corrected for albumin) with the calcium sensing receptor variant A986S in 102 healthy blood donors (P=0.45). CONCLUSIONS: The calcium-sensing receptor variants do not, therefore, seem to be major genetic determinants for the development of primary hyperparathyroidism. The variant A986S may possibly represent a risk factor for the development of parathyroid neoplasia in men. Moreover, the presence of the genotype Q1011E might influence the clinical course of the disease. The previously reported significant correlation of serum calcium levels with the genetic variant A986S in healthy subjects could not be confirmed.
M Bluher, K Krohn, H Wallaschofski, LE Braverman and R Paschke
OBJECTIVE: Apoptosis via the Fas pathway is a potential mechanism for thyroid tissue destruction leading to clinical hypothyroidism in Hashimoto's thyroiditis (HT). Recent studies reported contradictory results regarding the regulation of Fas/Fas ligand (FasL) expression by cytokines in vitro. We therefore determined the Fas and FasL gene expression in the BioBreeding/Worcester (BB/W) rat thyroiditis model, which can be regarded as a model for HT. METHODS: In order to obtain BB/W rats with spontaneous, iodine-induced or without lymphocytic thyroiditis (LT), rats were divided into 3 groups: 55-day-old rats after 24 days of iodine administration, 75-day-old rats after 45 days of iodine administration, and 101-day-old rats respectively. The gene expression of Fas, FasL, and interleukin (IL)-1beta was determined by Genescan fragment analysis using reverse polymerase chain reaction. Serum thyroglobulin (TG) antibody concentrations were measured and the extent of lymphocytic infiltration of one thyroid lobe was histologically graded. RESULTS: Fas and FasL gene expression was significantly higher in rats with LT and correlated with the extent of lymphocytic infiltration and the TG antibody level. There was no evidence that the expression of IL-1beta or other cytokines is related to the expression of Fas or its ligand. CONCLUSIONS: The increased expression of Fas and FasL in LT of BB/W rats suggests the involvement of the Fas pathway in the pathogenesis of LT in BB/W rats. However, in contrast to results of recent in vitro studies, in the BB/W rat Fas/FasL expression is not regulated by IL-2, -4, -6, -10, -12, interferon gamma, and tumor necrosis factor alpha.
R. Paschke, J. Teuber, U. Schwedes and K. H. Usadel
In several autoimmune diseases there is evidence for a possible role of antiidiotypic antibodies in the regulation of disease remission (Wasserman et al. 1982). In Graves' disease a significant increase in the incidence of circulating immune complexes in patients with negative TSI could be observed (Van der Heide et al. 1980). This finding has led to the suggestion that antiidiotypic antibodies may regulate the maintenance and re-establishment of a natural tolerance for the TSH-receptor.
Subsequently the production, biologic action and possible therapeutic implications of antiidiotypic antibodies in autoimmune thyroid disease could be demonstrated in two animal models (Zanetti et al. 1981; Islam et al. 1983). Recently antiidiotypic antibodies could be demonstrated in the sera of Graves' disease patients (Raines et al. 1985). Their presence correlated inversely with the presence of TSH receptor antibodies. To further elucidate the possible role of antiidiotypic antibodies for the regulation of remission in Graves' disease