[Lipodystrophy. Mechanisms, clinical presentation, therapy]. / Lipodystrophie. Mechanismen, Klinik, Therapie.

Lipodystrophy syndromes are a heterogenous group of congenital and acquired disorders with generalized or partial absence of subcutaneous adipose tissue. They are associated with severe metabolic abnormalities such as insulin resistance, diabetes mellitus, and hypertriglyceridemia that may result in life-threatening acute pancreatitis, steatohepatitis, and cardiovascular disease. Conventional lipid-lowering and antihyperglycemic medications may be insufficient to control severe metabolic abnormalities. The adipose tissue-derived hormone leptin has been investigated as a novel therapeutic option for severe lipodystrophy and significantly improves metabolic abnormalities in these patients. In Germany, leptin treatment for lipodystrophic patients with severe metabolic abnormalities is offered free of charge by the University Medicine Leipzig within a compassionate use program.

Multiple relapses of hyperthyroidism after thyroid surgeries in a patient with long term follow-up of sporadic non-autoimmune hyperthyroidism.

Constitutively activating thyrotropin receptor (TSHR) germline mutations have been identified as a molecular cause of congenital hyperthyroidism. Patients with relapsing hyperthyroidism were previously treated with surgery and radioiodine. We report on a 22-year-old male patient who was treated for his multiple relapses of hyperthyroidism by repeated subtotal thyroidectomies (STE). During the 22 years of follow-up, the patient developed several relapses of hyperthyroidism, four of them after thyroid surgeries. Sequencing of the TSHR gene revealed a gain-of-function mutation with an amino acid exchange of aspartate to tyrosine in codon 633 which is located in the sixth transmembrane domain of the TSH receptor. The absence of the mutation in all other family members identifies the patient's TSHR mutation as a sporadic germline mutation. In this patient, thyroid tissue growth and hyperthyroidism could repeatedly be controlled only for limited periods by near total thyroidectomy. Therefore, this case confirms that early combined treatment with near-total thyroidectomy plus radioiodine therapy seems to be the treatment of choice for patients with sporadic non-autoimmune hyperthyroidism.

Interobserver variation for ultrasound determination of thyroid nodule volumes.

Thyroid ultrasound is used in the routine clinical assessment and the follow-up of thyroid disorders. The follow- up of patients with thyroid nodules is mostly based on thyroid nodule volume determinations performed by different observers. However, for the judgment of treatment effects there is uncertainty about the interobserver variation of thyroid nodule volume measurements by ultrasound because there are no prospective blinded studies available comparing the interobserver variation in thyroid nodule volume measurement. The aim of our study was therefore to determine the variation of thyroid nodule volume determinations for different observers. We conducted a prospective blinded trial. Our study population consisted of 42 probands (8 men, 34 women) with an uniform distribution of thyroid nodule sizes (25 uninodular and 17 multinodular thyroid glands). We compared the results of 3 ultrasonographers with certified experience in thyroid ultrasound. The interobserver variation for the determination of thyroid nodule volume (n = 38) was 48.96% for the ellipsoid method and 48.64% for the planimetric method. The interobserver variation for determining thyroid volume (n = 40) was 23.69% for the ellipsoid method and 17.82% for the planimetric method. A regression analysis revealed that the probability for the identification of the same nodule in nodular thyroids by all sonographers is 90%, if the nodule is at least 15mm in greatest diameter. Future investigations should not describe changes in nodule volume less than 50% as therapy effects because only volume changes of at least 49% or more can be interpreted as nodule shrinkage or growth. Reporting of nodule volume modification 50% or more and lack of information for ultrasound procedures introduce a bias in studies evaluating the effects of nodule treatments. The clinical interpretation of a shrinking/growing thyroid nodule based on volume determinations by ultrasound is not well established because it is difficult to reproduce a two-dimensional image plane for follow-up studies.

Citalopram therapy as a risk factor for symptomatic hyponatremia caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH): a case report.

We report the case of an 81-year old woman with stupor, confusion, somnolence, vomiting, and reduced food intake for 5 days. Laboratory investigations revealed low serum concentrations of sodium and potassium with a serum osmolality of 225 mOsm/kg H (2)O in the face of an inappropriately concentrated urine with an osmolality in the normal range, suggesting the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the absence of renal insufficiency, adrenal insufficiency, and hypothyroidism. Careful drug evaluation revealed amitriptyline and citalopram as possible inciters of antidiuretic hormone secretion. Subsequently, these drugs were withdrawn. Under continuous sodium substitution and fluid restriction serum sodium normalized and the patient's symptoms resolved. She was fully alert by day 15. We conclude that hyponatremia secondary to SIADH was the cause of the patient's neurologic symptoms. Clinicians should be aware of this possible side effect of central acting agents such as amitriptyline and citalopram, drugs that are often used to treat elderly patients suffering from depression or chronic pain.

Therapy of hyperthyroidism.

Hyperthyroidism is a common disorder and affects approximately 2 % of women and 0.2 % of men. The review focuses on the therapy of overt hyperthyroidism with special emphasis on treatment strategies in Germany and Europe. Current treatment schedules for the different causes of hyperthyroidism are described and new therapeutic aspects are discussed. Special sections deal with the treatment of hyperthyroidism in pregnancy, neonates and children, and the treatment of thyrotoxic storm.

Prediction of remission or relapse for Graves' hyperthyroidism by the combined determination of stimulating, blocking and binding TSH-receptor antibodies after the withdrawal of antithyroid drug treatment.

The most likely reasons for the low predictive value of TSH-receptor antibodies (TRAbs) determinations in previous investigations are the biological heterogeneity of TRAbs and changes of the different stimulating (TSAb) or blocking (TSBAb) antibody bioactivities of TRAbs during the course of Graves' disease (GD), which have not been taken into account in most previous studies. Furthermore, in a recent study it has been demonstrated that the decline of TRAb values detected with highly sensitive hTBII or TSAB assays is not useful in evaluating remission or relapse of GD at the end of antithyroid drug treatment (ATDT). In order to make a thorough investigation of the predictive values of all different TRAb qualities for the recurrence for GD after the withdrawal, we investigated hTBII, TSAbs and TSBAbs in 54 consecutive patients with GD at the end of ATDT and 12 - 13.5 months after stopping ATDT. Using the TRAb values at the time of reinvestigation in a model, recurrence for GD was better predicted compared to the determination at the time of withdrawal of ATDT. Furthermore, using this model, the combined determination of hTBII, TSAbs, and TSBAbs revealed the highest level of significance for the prediction of remission or relapse of GD (OR = 15; p < 0.0001) compared to the detection of hTBII, TSAbs and TSBAbs alone. Therefore, significant changes of TSAbs after the end of ATDT and the biological heterogeneity of TRAb define the conditions for predicting remission or relapse of GD after ATDT by TRAb determinations. Consequently, our results suggest that the prediction of the individual course of GD can only be improved by combined determinations of all TRAb qualities (hTBII, TSAbs and TSBAbs) after the end of ATDT.

Distinction between autoimmune and non-autoimmune hyperthyroidism by determination of TSH-receptor antibodies in patients with the initial diagnosis of toxic multinodular goiter.

Distinguishing Graves' disease (GD) from a toxic multinodular goiter (TMG) subgroup with a diffuse but uneven Tc-distribution depends on the diagnostic power of the TSH-receptor antibody (TRAb) determination. Bioassays using CHO cell lines expressing the hTSH-receptor or a new TBII assay, which uses the hTSH-receptor as an antigen (DYNOTEST TRAK human, Brahms, Germany), showed a higher sensitivity for the detection of TRAbs in patients with GD than assays using solubilized porcine epithelial cell membranes. The aim of this study was to investigate whether the new Dynotest TRAK human assay has an increased sensitivity to distinguish GD from non-autoimmune hyperthyroidism. Therefore, we examined 21 consecutive patients with the initial diagnosis of TMG for thyroid-stimulating antibodies (TSAbs, JP26 cell assay) and TBII with the new highly sensitive Dynotest TRAK human (Brahms, Germany). The initial diagnosis of TMG was based on suppressed TSH and a patchy Tc-uptake of more than 1 % and less than 7 % or TSH of more than 0.3 mIE/l with a patchy Tc-uptake of more than 1.5 % and less than 7 % and negative TBII values in a displacement assay using solubilized porcine epithelial cell membranes (TRAK, Brahms, Germany). 11 sera from these 21 patients showed TSAb activity. Furthermore, 10 of these 11 TSAb-positive sera were also positive in the Dynotest TRAK human assay, whereas one serum sample was borderline positive. TSAb activity and inhibition of (125)I-bTSH binding in the Dynotest TRAK human assay correlated well (r = 0.7). Therefore, 11 of the 21 investigated patients initially classified as TMG actually had GD, which was undetectable using the porcine TBII assay. In conclusion, TSAbs or TRAbs detected with the Dynotest TRAK human have the highest diagnostic power to differentiate GD from TMG. Because of the less cumbersome assay technique, the Dynotest TRAK human measurements should be obtained for all patients with non-typical TMG to differentiate GD from non-autoimmune hyperthyroidism in order to select the appropriate therapy for these patients.

Differences between thyrotropin receptor antibody bioactivity and inhibition of 125I-bovine thyrotropin binding.

Thyrotropin (TSHR) receptor antibodies that bind to the TSHR without stimulating the TSHR have been identified with a direct binding assay. Moreover, TSHR antibodies that exhibit thyroid epithelial cell stimulation without inhibition of 125I-bovine thyrotropin (bTSH) binding and vice versa have been described. These data suggest that stimulation or blocking of the TSHR by stimulating (TSAB) or blocking (TSBAB) TSHR antibodies could be possible without detectable bTSH-displacement activity. However, to date, possible differences between TSAB or TSBAB activity and inhibition of 125I-bTSH binding have not been systematically investigated. Therefore we compared inhibition of 125I-bTSH binding and TSAB or TSBAB activity of sera from 113 patients with Graves' disease treated with antithyroid drugs. To exclude the different assay conditions of previous investigations as possible confounding factors, we determined TSAB or TSBAB and inhibition of 125I-bTSH binding (TBIIW) with the same Chinese hamster ovary (CHO) cells expressing the human TSHR. Furthermore inhibition of 125I-bTSH binding was also determined as thyrotropin-binding inhibitory immunoglobulin (TBII) with solubilized porcine thyroid membranes (TRAK, Brahms, Berlin Germany) and the highly sensitive recombinant human TSH receptor assay (hTRAK, Brahms, Berlin Germany). Only 78% (54/69) of TSAB-positive and 78% (21/27) of TSBAB-positive sera detected with JP26 cells exhibit inhibition of 125I-bTSH binding measured as TBII or TBIIW. Furthermore, 59% (10/17) of sera without TSAB and TSBAB activity revealed inhibition of 125I-bTSH binding measured as TBII or TBIIW. We found significant differences between TSHR bioactivities (TSAB or TSBAB) and inhibition of 125I-bTSH binding. Moreover, there was no agreement between the detectable TSHR bioactivities (TSAB or TSBAB) and their detectable inhibition of 125I-bTSH binding. Therefore, it is very likely that TSH displacement by TSHR antibodies and stimulation or blocking of the TSHR by TSHR antibodies are different functions that do not need to occur together.