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K Jungheim, K Badenhoop, OG Ottmann and KH Usadel

Hypothalamic disease often affects the patients' personality and this also applies to pituitary tumors with suprasellar extension. We report on a patient with a 12-year history of recurrent acromegaly, treated with three transphenoidal operations, single field radiation therapy and bromocriptine/octreotide administration. During the course of follow-up she presented with self-inflicted anemia and Kleine-Levin syndrome (hypersomnia, hyperphagia and hypersexuality). Furthermore, she developed post-radiation necrosis within the right temporal lobe. Whether her neurological and personality disorders result - at least partially - from the acromegaly or the temporal lobe necrosis remains unclear.

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MA Pani, J Seissler, KH Usadel and K Badenhoop

OBJECTIVE: Autoimmune Addison's disease is a rare disorder which results from the T cell-mediated destruction of adrenocortical cells. A number of genetic susceptibility markers are shared by Addison's disease, type 1 diabetes, Graves' disease and Hashimoto's thyroiditis. The vitamin D endocrine system has been shown to influence immune regulation. Variants of the nuclear vitamin D receptor (VDR) gene were found to be associated with type 1 diabetes and thyroid autoimmunity amongst others. We therefore investigated the role of VDR polymorphisms in Addison's disease. DESIGN AND METHODS: Patients (n=95) and controls (n=220) were genotyped for VDR polymorphisms FokI, BsmI, ApaI and TaqI. RESULTS: The 'ff' (13.7% vs 5.5%; P=0.0243; odds ratio = 2.75) and the 'tt' (28.4% vs 14.1%; P=0.0043; odds ratio = 2.42) genotypes were significantly more frequent in patients than in controls. Furthermore, the BsmI genotype distribution differed significantly between patients and controls (chi(2)=6.5016 (2 d.f.) P=0.0387). CONCLUSIONS: These data suggest that the VDR genotype is associated with Addison's disease. The mechanisms by which distinct receptor variants might confer disease susceptibility remain to be elucidated.

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K. BADENHOOP, J. TROWSDALE, G. SCHWARZ, E. GALE, K. H. USADEL and G. F. BOTTAZZO

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K. BADENHOOP, V. LEWIS, V. DRUMMOND, H. SCHLEUSENER, K. H. USADEL, G. SCHWARZ and G. F. BOTTAZZO

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BJ Stuck, MA Pani, F Besrour, M Segni, M Krause, KH Usadel and K Badenhoop

BACKGROUND: Apoptosis is a joint pathogenic process underlying autoimmune thyroid disease. Increased programmed cell death in thyrocytes causes hypothyroidism in Hashimoto's thyroiditis, whereas in Graves' disease infiltrating lymphocytes undergo apoptosis while thyrocytes appear to proliferate under protection of anti-apoptotic signals. The Fas/Fas ligand cascade represents a major pathway initiating apoptosis. Its role in autoimmunity is well studied and genetic polymorphisms in gene loci of Fas and its ligand have been shown to be associated with autoimmune diseases. OBJECTIVE: Due to the functional relevance of the Fas pathway in autoimmune thyroid disease we were interested in the possible contribution of polymorphisms in the Fas gene to the genetic risk of thyroid autoimmunity, which so far is mainly, but incompletely, attributed to the HLA DQ region and polymorphisms in the CTLA-4 gene. DESIGN: We genotyped Caucasian families with at least one offspring affected by Hashimoto's thyroiditis (n=95) and Graves' disease (n=109) for two Fas gene polymorphisms (g-670 G-->A in the promoter region, g-154 C-->T in exon 7). METHODS: Extended transmission disequilibrium and chi(2) testing were performed. RESULTS: Neither polymorphism alone (P=0.44 and P=0.70) nor the promoter/exon 7 haplotypes (P=0.86) were associated with Hashimoto's thyroiditis. No association with Graves' disease was observed for the promoter polymorphism (P=0.91) and exon 7 (P=0.65) or the promoter/exon 7 haplotypes (P=0.80). CONCLUSION: In summary, our data do not suggest any significant contribution of common genetic Fas variants to the genetic risk of developing Hashimoto's thyroiditis or Graves' disease.

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MA Pani, K Regulla, M Segni, M Krause, S Hofmann, M Hufner, J Herwig, AM Pasquino, KH Usadel and K Badenhoop

OBJECTIVE: The vitamin D endocrine system plays a role in the regulation of (auto)immunity and cell proliferation. Vitamin D 1alpha-hydroxylase (CYP1alpha) is one of the key enzymes regulating both systemic and tissue levels of 1,25-dihyroxyvitamin D(3) (1,25(OH)(2)D(3)). Administration of 1,25(OH)(2)D(3), whose serum levels were found to be reduced in type 1 diabetes and thyroid autoimmunity, prevents these diseases in animal models. We therefore investigated a recently reported CYP1alpha polymorphism for an association with type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. DESIGN AND METHODS: Four hundred and seven Caucasian pedigrees with one offspring affected by either type 1 diabetes (209 families), Graves' disease (92 families) or Hashimoto's thyroiditis (106 families) were genotyped for a C/T polymorphism in intron 6 of the CYP1alpha gene on chromosome 12q13.1-13.3 and transmission disequilibrium testing (TDT) was performed. Subsets of affected offspring stratified for HLA-DQ haplotype were compared using chi(2) testing. RESULTS: There was no deviation from the expected transmission frequency in either type 1 diabetes mellitus (P=0.825), Graves' disease (P=0.909) or Hashimoto's thyroiditis (P=0.204). However, in Hashimoto's thyroiditis the CYP1alpha C allele was significantly more often transmitted to HLA-DQ2(-) patients (27 transmitted vs 14 not transmitted; TDT: P=0.042) than expected. The C allele was less often transmitted to HLA-DQ2(+) patients (9 transmitted vs 12 not transmitted; TDT: P=0.513), although the difference was not significant (chi(2) test: P=0.143). A similar difference was observed in type 1 diabetes between offspring with high and low risk HLA-DQ haplotypes (chi(2) test: P=0.095). CONCLUSIONS: The CYP1alpha intron 6 polymorphism appears not to be associated with type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. A potential association in subsets of patients with type 1 diabetes and Hashimoto's thyroiditis should be further investigated as well as its functional implications.

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H. Schleusener, J. Schwander, G. Holl, K. Badenhoop, J. Hensen, R. Finke, G. Schernthaner, W. R. Mayr and P. Kotulla

Abstract. In patients with Graves' hyperthyroidism, the relapse rate after antithyroid drug treatment is in the range of about 30–70%. Different attempts have been made to obtain criteria for the prediction of the clinical outcome after drug therapy, especially HLA-DR typing and measurement of TSH receptor antibodies. So far, very conflicting results have been reported. This is not surprising in view of the many genetically controlled and environmental factors that play a role in the pathogenesis of this disease. Moreover, most reports are based on retrospective studies with a relatively small number of patients. Our own data, obtained in a prospective multicenter study, yield strong evidence against the relevance of HLA-DR3 typing (n = 187, sensitivity = 0.38, specificity = 0.67) or measurement of TSH receptor antibodies at the end of therapy (n = 269, sensitivity = 0.49, specificity = 0.72) for the prediction of the clinical course after drug treatment.

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ER Lopez, O Zwermann, M Segni, G Meyer, M Reincke, J Seissler, J Herwig, KH Usadel and K Badenhoop

BACKGROUND: CYP27B1 hydroxylase catalyzes the conversion of 25 hydroxyvitamin D(3) (25OHD(3)) to 1,25(OH)(2)D(3), the most active natural vitamin D metabolite, which plays a role in the regulation of immunity and cell proliferation. We therefore investigated two single nucleotide polymorphisms in the CYP27B1 hydroxylase gene for an association with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus. METHODS: Patients with Addison's disease (n=124), Hashimoto's thyroiditis (n=139), Graves' disease (n=334), type 1 diabetes mellitus (n=252) and healthy controls (n=320) were genotyped for the promoter (-1260) C/A polymorphism and for the intron 6 (+2838) C/T polymorphism of the CYP27B1 gene. Patients and controls were compared using genotype-wise and allele-wise X(2) testing. RESULTS: A significant association was found between allelic variation of the promoter (-1260) C/A polymorphism and Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus (P=0.0062, P=0.0173, P=0.0094 and P=0.0028 respectively). Significant differences were also observed for the intron 6 (+2838) C/T polymorphism (P=0.0058) in Hashimoto's thyroiditis but not for the other autoimmune endocrine diseases. CONCLUSIONS: The CYP27B1 promoter (-1260) C/A polymorphism appears to be associated with endocrine autoimmune diseases but the CYP27B1 intron 6 (+2838) C/T polymorphism appears to be associated only with Hashimoto's thyroiditis. These results imply a regulatory difference of the CYP27B1 hydroxylase to predispose to endocrine autoimmunity.