[Iodine-induced thyroid dysfunction]. / Jodinduzierte Schilddrüsendysfunktion.

BACKGROUND: Iodine-induced thyroid dysfunctions are, despite their rare occurrence, important clinical syndromes. Their immediate recognition can avoid serious consequences. Important triggers can be iodine-containing contrast agents, amiodarone or iodine-containing disinfectants. Iodine-induced hypothyroidism and hyperthyroidism need to be distinguished, whereby the former is usually self-limiting. OBJECTIVES: The aim of this article is to present current knowledge on the pathogenesis, therapy, and prophylaxis of iodine-induced thyroid dysfunction. MATERIALS AND METHODS: We performed a literature search of current publications and linked them to daily clinical experience. RESULTS AND CONCLUSION: In iodine-induced hyperthyroidism, antithyroid drugs and perchlorate are primarily used to decrease thyroid hormone synthesis and further iodine uptake into the thyroid. For the prophylaxis of x­ray contrast agent-induced hyperthyroidism, perchlorate can be administered in high-risk settings in combination with antithyroid drugs, if possible starting one day before the iodine exposure.

[Autoimmune diseases of the thyroid gland]. / Autoimmune Schilddrüsenerkrankungen.

Autoimmune diseases of the thyroid gland are considered to be the most frequent cause of thyroid gland disorders. Autoimmune thyroid diseases consist of two subgroups: autoimmune thyroiditis (AIT) and Graves' disease. The AIT is the most common human autoimmune disease. Infiltration of the thyroid gland with cytotoxic T­cells can lead to an initial thyrotoxicosis und during the course to hypothyroidism due to destruction of the thyroid gland. Substitution with Levothyroxine is indicated for manifest hypothyroidism and subclinical hypothyroidism with increased thyroid antibodies with the intention of normalizing the serum thyroid stimulating hormone (TSH). Graves' disease is characterized by the appearance of stimulating TSH receptor antibodies leading to hyperthyroidism. Endocrine ophthalmopathy may also occur. Ablative therapy with radioiodine therapy or thyroidectomy is administered to patients with Graves' disease without remission after at least 1 year of antithyroid drug therapy.

Clinical Evaluation of the First Automated Assay for the Detection of Stimulating TSH Receptor Autoantibodies.

Until recently, stimulating TSH receptor autoantibodies (sTRAbs) could only be measured by bioassays. A new assay system, which directly detects sTRAb in sera by applying bridge technology, has been established and is now available as automated chemiluminescence (bridge) immunoassay. We evaluated the automated bridge assay in clinical routine and compared it with a conventional automated TRAb assay (competition assay). Altogether, 226 Graves' disease (GD), 57 autoimmune thyroiditis, 74 non-autoimmune nodular goiter and 49 thyroid cancer patients, as well as 41 healthy controls were retrospectively evaluated. ROC plot analysis based on sera of newly diagnosed GD patients revealed an area under curve of 0.99 (95% CI: 0.99-1.0) indicating a high assay sensitivity and specificity. The highest sensitivity (100%) and specificity (99%) were seen at a cut-off level of 0.55 IU/l. The calculated positive predictive value was 94%, whereas the negative was 100%. Applying a ROC plot-derived cut-off of≥0.30 IU/l, derived from sera of GD patients already receiving antithyroid drug therapy for≤6 months, the sensitivity was 99% whereas the specificity was 98%. Detailed comparison of both assay systems used revealed a slightly different distribution of sTRAb and TRAb. Measurement of sTRAb during follow-up revealed a steady decline over one year of follow-up. In summary, our results demonstrate that the new automated bridge assay system for detecting sTRAb has a high sensitivity and specificity for diagnosing GD and to discriminate from other thyroid diseases, respectively. Our study, however, does not provide full evidence that the bridge assay is specific for sTRAb only.

Anti-Thyroperoxidase Antibody Levels >500 IU/ml Indicate a Moderately Increased Risk for Developing Hypothyroidism in Autoimmune Thyroiditis.

Autoimmune Thyroiditis (AIT) is the most common autoimmune disease, which is characterized by cellular and humoral immunity leading to thyroid destruction. The impact of the humoral immunity on the risk to develop hypothyroidism has not exactly been defined yet. The aim of the present study was to investigate the association between thyroid antibody levels and the risk for developing hypothyroidism. In this retrospective study, 335 untreated AIT patients were enrolled. Anti-thyroperoxidase (TPO) antibodies, anti-thyroglobulin (Tg) antibodies (Abs), and the TSH level were measured. Patients with TPO-Ab levels>500 IU/ml showed a moderately increased risk of having elevated TSH levels [p=0.0023; relative risk (95% confidence interval): 1.343 (1.108-1.627)] compared to those below this threshold. AIT patients with TPO- or Tg-Abs<100 IU/ml and between 100-500 IU/ml had no significantly different TSH levels. Presence of Tg-Abs alone or in combination with TPO-Abs did not help to increase the sensitivity to identify patients at risk. Long term follow-up of AIT patients with high TPO-Abs level (>500 IU/ml) showed an increase of TSH levels (mean: 0.5 mIU/l; range: 2.52±2.73 to 3.02±3.05 mIU/l; p=0.0420). Still, these patients remained euthyroid. Our data indicate largely elevated levels of TPO-Abs being associated with a moderately increased risk of developing hypothyroidism.

[The Choosing Wisely Initiative of the German Society of Internal Medicine : Recommendations of the German Society for Endocrinology and the German Society for Geriatrics]. / Die Klug-entscheiden-Initiative der Deutschen Gesellschaft für Innere Medizin : Empfehlungen der Deutschen Gesellschaft für Endokrinologie und der Deutschen Gesellschaft für Geriatrie.

POSITIVE RECOMMENDATIONS: A. After osteoporotic fractures in the elderly, as a rule specific antiosteoporotic therapy should be initiated. a. Osteoporosis as a disease of the elderly should be diagnosed and treated (recommendation of the German Society for Geriatrics). B. All patients with diabetes mellitus should complete a specific diabetes training program when antidiabetic drug medication is initiated. C. In Germany, all pregnant women should be advised to undertake iodine supplementation. D. Endocrine causes of hypertension should be ruled out in younger patients and in patients on multiple antihypertensive drugs. E. All unclear cases of hypercalcemia should be clarified. NEGATIVE RECOMMENDATIONS: A. Testosterone substitution therapy should not be initiated on the basis of only one measurement of a reduced testosterone level without clinical signs and clarification of the underlying cause. B. Imaging procedures should only be used after the existence of hormonal disease has been confirmed. C. Sonographic screening for thyroid disease is not advised in the elderly. D. Long-term therapy with levothyroxine for nodular goiter should be avoided. E. In relevant stress situations hydrocortisone replacement therapy should not be continued without dose adjustment in patients with adrenal or pituitary insufficiency.

[Thyroid dysfunction in pregnancy]. / Schilddrüsenfunktionsstörungen in der Schwangerschaft.

Thyroid dysfunction may impair fertility, course of pregnancy and fetal development. Physiological alterations of thyroid function parameters, that occur during pregnancy need to be distinguished from pathophysiological states of hypo- and hyperthyroidism. We performed a literature search (PubMed 1990-2013) and review relevant publications as well as consensus and practice guidelines of international thyroid/endocrine societies. Interpretation of thyroid function values in pregnancy must be based on trimester-specific TSH and T4 ranges. Alterations in thyroid function are present in up to 15% of pregnancies (0.4% overt hypothyroidism, 0.1-0.4% hyperthyroidism) and may lead to preventable complications in the pregnant woman and the fetus. Hypothyroidism is associated with an increased risk for abortion, premature delivery and stillbirth, besides impairment of neurocognitive development. The latter has also been shown in situations of grave iodine deficiency. In addition to new-born screening directed at early recognition of congenital hypothyroidism (incidence 0.03%), universal screening of all pregnant women should be implemented in health care guidelines. Newly diagnosed overt hypothyroidism in a pregnant woman requires immediate levothyroxine substitution at adequate doses. In subclinical hypothyroidism thyroid hormone replacement should be considered. Iodine supplementation is strongly recommended in all pregnant and breast-feeding women. Pregnancy causes a number of, that need to be of thyroid dysfunction. Both hypothyroidism and thyrotoxicosis may impair the course of pregnancy and may negatively affect the fetus. In particular, maternal hypothyroidism may lead to irreparable and detrimental deficits in the neurocognitive development of the fetus. Autoimmune thyroid disease is the most common cause of thyroid dysfunction in pregnancy. Hashimoto's thyroiditis is associated with impaired fertility and miscarriage, and may first manifest in pregnancy due to the increased thyroid hormone requirement. Graves' disease often shows a characteristic course in pregnancy with amelioration of thyrotoxicosis in the second half of pregnancy and exacerbation after delivery. In addition transplacental passage of maternal TSH receptor antibodies may lead to thyrotoxicosis in the fetus and/or newborn.

Ultrafast X-ray probing of water structure below the homogeneous ice nucleation temperature.

Water has a number of anomalous physical properties, and some of these become drastically enhanced on supercooling below the freezing point. Particular interest has focused on thermodynamic response functions that can be described using a normal component and an anomalous component that seems to diverge at about 228 kelvin (refs 1-3). This has prompted debate about conflicting theories that aim to explain many of the anomalous thermodynamic properties of water. One popular theory attributes the divergence to a phase transition between two forms of liquid water occurring in the 'no man's land' that lies below the homogeneous ice nucleation temperature (TH) at approximately 232 kelvin and above about 160 kelvin, and where rapid ice crystallization has prevented any measurements of the bulk liquid phase. In fact, the reliable determination of the structure of liquid water typically requires temperatures above about 250 kelvin. Water crystallization has been inhibited by using nanoconfinement, nanodroplets and association with biomolecules to give liquid samples at temperatures below TH, but such measurements rely on nanoscopic volumes of water where the interaction with the confining surfaces makes the relevance to bulk water unclear. Here we demonstrate that femtosecond X-ray laser pulses can be used to probe the structure of liquid water in micrometre-sized droplets that have been evaporatively cooled below TH. We find experimental evidence for the existence of metastable bulk liquid water down to temperatures of 227(-1)(+2) kelvin in the previously largely unexplored no man's land. We observe a continuous and accelerating increase in structural ordering on supercooling to approximately 229 kelvin, where the number of droplets containing ice crystals increases rapidly. But a few droplets remain liquid for about a millisecond even at this temperature. The hope now is that these observations and our detailed structural data will help identify those theories that best describe and explain the behaviour of water.

[Subclinical hyperthyroidism]. / Subklinische Hyperthyreose.

Subclinical hyperthyroidism is defined as abnormal low TSH level with thyroid hormones within their reference range. This laboratory condition may be symptomatic in a relevant number of patients leading to tachycardia, sweating, nervousness, anxiety and insomnia. The risk for cardiovascular disease is increased with more frequent atrial fibrillation and increased left ventricular mass including diastolic dysfunction. Cardiovascular mortality and overall mortality surmounts the average of the normal population. Longterm TSH suppression leads to decreased bone mineral density and an increased fracture rate in the hip and in the spine. After evaluation of underlying causes, therapy should be considered, especially if TSH levels are below 0.1 mIU/l.

X-ray parametric down-conversion in the Langevin regime.

We experimentally and theoretically study the coincidence count rate for down-converted x-ray photons. Because of photoionization, parametric down-conversion at x-ray wavelengths generally involves loss and the theoretical description requires a Langevin approach. By working in a transmission geometry (Laue) rather than in the Bragg geometry of previous experiments, we obtain an improvement in the signal-to-noise ratio of 12.5, and find agreement between experiment and theory.

X-ray and optical wave mixing.

Light-matter interactions are ubiquitous, and underpin a wide range of basic research fields and applied technologies. Although optical interactions have been intensively studied, their microscopic details are often poorly understood and have so far not been directly measurable. X-ray and optical wave mixing was proposed nearly half a century ago as an atomic-scale probe of optical interactions but has not yet been observed owing to a lack of sufficiently intense X-ray sources. Here we use an X-ray laser to demonstrate X-ray and optical sum-frequency generation. The underlying nonlinearity is a reciprocal-space probe of the optically induced charges and associated microscopic fields that arise in an illuminated material. To within the experimental errors, the measured efficiency is consistent with first-principles calculations of microscopic optical polarization in diamond. The ability to probe optical interactions on the atomic scale offers new opportunities in both basic and applied areas of science.

Structure and flow of droplets on solid surfaces.

The structure and flow of droplets on solid surfaces is investigated with imaging and scattering techniques and compared to simulations. To access nanostructures at the liquid-solid interface advanced scattering techniques such as grazing incidence small-angle x-ray scattering (GISAXS) with micro- and nanometer-sized beams, GISAXS and in situ imaging ellipsometry and GISAXS tomography are used. Using gold nanoparticle suspensions, structures observed in the wetting area due to deposition are probed in situ during the drying of the droplets. After drying, nanostructures in the wetting area and inside the dried droplets are monitored. In addition to drying, a macroscopic movement of droplets is caused by body forces acting on an inclined substrate. The complexity of the solid surfaces is increased from simple silicon substrates to binary polymer brushes, which undergo a switching due to the liquid in the droplet. Nanostructures introduced in the polymer brush due to the movement of droplets are observed.

[Autoimmune thyroiditis: diagnosis and treatment]. / Autoimmunthyreoiditis: Diagnostik und Therapie.

Autoimmune thyroiditis (AIT) is an autoimmune disease with genetic background. Women are more likely to develop AIT. In adulthood, AIT is the most frequent cause for acquired hypothyroidism. Cytotoxic T-lymphocyte antigen (CTL-4) may play a role in the etiology of the disease. Diagnosis is made by determination of elevated antibodies against thyroid peroxidase and thyroglobulin, and a hypoechoic pattern in ultrasound. In case of hypothyroidism a substitutive therapy with levothyroxine is necessary. AIT may occur as postpartum thyroiditis or as a special entity as consequence of therapy with cytokines.

Coherent x-ray diffraction imaging with nanofocused illumination.

Coherent x-ray diffraction imaging is an x-ray microscopy technique with the potential of reaching spatial resolutions well beyond the diffraction limits of x-ray microscopes based on optics. However, the available coherent dose at modern x-ray sources is limited, setting practical bounds on the spatial resolution of the technique. By focusing the available coherent flux onto the sample, the spatial resolution can be improved for radiation-hard specimens. A small gold particle (size <100 nm) was illuminated with a hard x-ray nanobeam (E=15.25 keV, beam dimensions approximately 100 x 100 nm2) and is reconstructed from its coherent diffraction pattern. A resolution of about 5 nm is achieved in 600 s exposure time.

Comparison of a solid phase human- versus porcine- thyrotropin receptor-based immunoassay for the measurement of thyrotropin receptor antibodies in patients with thyroid diseases.

Thyrotropin receptor (TSHR) antibody (TRAb) assays based on human or porcine TSHR which are coated to a solid phase are the most commonly used detection methods in clinical practice for patients with thyroid diseases. Yet the difference of the diagnostic values of the two TRAb assays is largely unclear. The aim of our present study was to evaluate the clinical perfomance of a solid phase porcine TRAb assay based on an ELISA technique (TRAb-porcine) and a human TRAb assay based on a chemiluminescence signal detection procedure (TRAb-human). Of 158 patients enrolled in the study, 84 suffered from Graves' disease (GD), 34 had Hashimoto's thyroiditis (HT) and 40 had euthyroid nodular thyroid disease (NTD) without signs of autoimmunity. TRAb measurements were performed according to the manufacturer's instructions. The mean values of TRAb titers detected by the TRAb-human and TRAb-porcine assays in patients with GD were 12.14+/-10.80 IU/L and 15.27+/-13.65 IU/L, respectively. TRAb were detected in 80 and 78 out of 84 GD patients by the TRAb-human and TRAb-porcine assay, respectively. The diagnostic sensitivity of the TRAb-human and TRAb-porcine immunoassay was 95.2 and 92.9% respectively, by 100% specificity of both methods. TRAb values in GD patients detected by the TRAb-human and TRAb-porcine assays were significantly correlated (r=0.929, p<0.0001). Our results indicate that the second generation TRAb-porcine assay based on solid phase technology had a slightly lower diagnostic sensitivity compared to the TRAb-human assay.

Expression and mutation analysis of the tyrosine kinase c-kit in poorly differentiated and anaplastic thyroid carcinoma.

Poorly differentiated and anaplastic thyroid carcinoma are aggressive tumors failing to res-pond to conventional therapy. Imatinib mesylate offers an effective therapeutic option in patients with various types of malignancies by inhibiting tyrosine kinases such as c-kit. In this study we investigated c-kit expression in anaplastic and poorly differentiated thyroid carcinoma compared to differentiated carcinoma and adenoma and the presence of c-kit mutations. In total, 224 thyroid tissues were analyzed by immunohistochemistry. Mutation analysis of exon 9, 11, 13, and 17 of the c-kit gene was performed in anaplastic and poorly differentiated carcinoma. c-Kit expression was negative in all anaplastic thyroid carcinoma, while c-kit expression of poorly differentiated carcinoma showed a high variability with a more intense staining in tumors showing obvious differentiated malignant follicular tumor areas. Differentiated carcinoma showed a slight, but not significantly stronger c-kit expression than poorly differentiated carcinoma. All tumors revealed wild type sequences of c-kit gene in exons 9, 11, 13, and 17. The low or lacking c-kit expression in undifferentiated thyroid carcinoma together with the lack of mutations argue against a crucial role of c-kit in thyroid carcinoma cell proliferation. Further molecular targets of imatinib mesylate have to be analyzed to estimate a potential benefit of this drug for patients with dedifferentiated thyroid carcinoma.

Compact x-ray microtomography system for element mapping and absorption imaging.

We have designed and built a compact x-ray microtomography system to perform element mapping and absorption imaging by exploiting scanning fluorescence tomography and full-field transmission microtomography, respectively. It is based on a low power microfocus tube and is potentially appropriate for x-ray diagnostics in space. Full-field transmission tomography yields the three-dimensional inner structure of an object. Fluorescence microtomography provides the element distribution on a virtual section through the sample. Both techniques can be combined for appropriate samples. Microradiography as well as fluorescence mapping are also possible. For fluorescence microtomography a small and intensive microbeam is required. It is generated using a polycapillary optic. Operating the microfocus tube with a molybdenum target at 12 W, a microbeam with a full width at half maximum lateral extension of 16 microm and a flux of about 10(8) photonss is generated. As an example of application, this beam is used to determine the element distribution inside dried plant samples. For full-field scanning tomography, the x-ray optic is removed and the sample is imaged in magnifying projection onto a two-dimensional position sensitive detector. Depending on the sample size, a spatial resolution down to about 10 microm is possible in this mode. The method is demonstrated by three-dimensional imaging of a rat humerus.

Relevance of TSH receptor stimulating and blocking autoantibody measurement for the prediction of relapse in Graves' disease.

Recently, we demonstrated that higher levels of autoantibodies to the human TSH receptor (TBII) predict relapse of hyperthyroidism in Graves' disease (GD). The aim of this study was to extend this outcome prediction by dividing TBII into stimulating (TSAb) and blocking (TBAb) TSH receptor autoantibodies. Altogether, ninety patients (81 female, 9 male) were retrospectively analyzed; sixty-four patients (71 %) did not go into remission or relapsed, whereas twenty-six patients (29 %) went into remission (median follow-up: 17.5 months). TSAb and TBAb measurement was performed in a CHO cell bioassay with cAMP readout at the time of their first visit in our outpatient clinic (single point measurement in median 6.5 months after initial diagnosis). In the remission group, eighteen of twenty-six patients (69 %) were TSAb-positive, whereas fifty-three of sixty-four patients (83 %) were TSAb-positive in the relapse group (p = ns). The mean stimulation indices (SI) were 4.1 in the remission group and 12.9 in the relapse group, respectively (p = 0.015). By using a threshold of 10 SI, the specificity for relapse was 96.0 %, as only one in twenty patients with an SI above 10 went into remission during follow-up (PPV 95 %). Most TSAb-positive patients also had high levels of TBII. Neither group showed any difference with respect to blocking type autoantibodies, which were mostly negative in both groups. In summary, high TSAb levels are similar but not superior to TBII for predicting relapse in GD patients. In contrast, TBAb measurement does not add any valuable information in this context. In the clinical routine, TSAb/TBAb measurement may not play an important role for diagnosis or outcome prediction of GD, since sensitive 2 (nd) generation TBII assays are easier to perform and offer similar information to the clinician. Bioassays should be reserved for special clinical questions such as Graves' disease in pregnancy.

Prediction of relapse after antithyroid drug therapy of Graves' disease: value of color Doppler sonography.

Opinions differ regarding the indications for antithyroid drugs, radioiodine and surgery in patients with Graves' disease because the likelihood of long-term remission after medical treatment cannot be predicted. The aim of this study was to assess the value of quantifying thyroid blood flow in an attempt to predict outcome following withdrawal of antithyroid drug therapy. Spectral Doppler recordings were obtained from the thyroid arteries in 24 patients with Graves' disease at the time of diagnosis. Thyroid blood flow levels measured at the time of diagnosis of Graves' disease were correlated with outcome following withdrawal of medical treatment (mean duration of treatment: 14 months). Clinical follow-up for at least 18 months (range: 18 - 39 months) after antithyroid drug withdrawal was possible in 13 patients (12 women). Mean peak systolic velocity and volume flow rate values as well as thyroid volume measured at the time of diagnosis were significantly higher (139 cm/s, SD 46; 195 ml/min, SD 170; 52 ml, SD 18) in patients who relapsed after drug treatment compared with patients in remission (71 cm/s, SD 27; 67 ml/min, SD 61; 25 ml, SD 13). The correlation between thyroid blood flow measurements and thyroid volume was high (r = 0.79 - 0.96). Recurrence of disease could be predicted with a sensitivity of 71 % and a specificity of 100 % based on thyroid blood flow measurements. This preliminary data suggest that quantification of thyroid blood flow by means of Doppler sonography might be a useful tool to predict the outcome of Graves' disease following withdrawal of medical treatment and could be helpful in finding the adequate kind of therapy.

Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves' disease.

The aim of this study was to evaluate the ability of the more sensitive second-generation TSH receptor (TRAb) assay to predict recurrent Graves' disease (GD) vs. remission depending on TRAb levels. 93 patients with active GD were included in the study. By using a cut-off limit of 1.0 IU/l, all 93 patients were positive for TRAb (median: 4.6 IU/l) at the time of their first visit (single point measurement in median 5.1 months after initial diagnosis). Subsequently, 33 patients went into remission and were euthyroid during follow-up (median follow-up: 21.7 months), whereas 60 patients did not go into remission or developed relapse over the following 24 months. Median TRAb levels in the group of remission were significantly (p < 0.0001) lower than TRAb values in the relapse group (2.1 compared to 8.6 IU/l). Applying ROC plot analysis to compare different TRAb thresholds, a cut-off of 10 IU/l was established. Here, the specificity for relapse was 97 % as only 1 of 29 patients with TRAb values above 10 IU/l went into remission during follow-up, whereas all other 28 patients developed a relapse (positive predictive value for relapse: 96.4 %). In contrast, TRAb values lower than 10 IU/l had no impact on the prediction of remission. In conclusion, our data clearly indicate that TRAb measurement is useful for identifying patients that will not benefit from long-term antithyroid drug treatment.

Pheochromocytoma during pregnancy: laparoscopic and conventional surgical treatment of two cases.

Pheochromocytoma is a rare entity. When it presents during pregnancy, rapid recognition and diagnosis are crucial in order to avoid the maternal and fetal morbidity and mortality associated with severe, uncontrolled hypertension. Difficulties arise from the differential diagnosis of pre-eclampsia. We report two patients operated on for pheochromocytoma during pregnancy. The first patient developed new-onset hypertension in early pregnancy. Prior to presentation, there had been non-specific signs of endocrine disorder, namely a mild diabetes, but no hypertension requiring medication. The second patient sought medical care for irregular heartbeat, shortness of breath, and fatigue during the 6th week of pregnancy. She was found to be hypertensive; diagnostic evaluation revealed substantially increased catecholamine levels. The diagnosis was made by elevated urinary catecholamines and by MRI scan as well as ultrasonography, both of which demonstrated an adrenal mass. Both patients underwent surgical extirpation of the affected adrenal gland. The procedure was performed laparoscopically in the case of the second patient. Pre-operatively, both patients were pre-treated with alpha-blockade followed by secondary beta-blockade. Patient two also received methyldopa for control of hypertension. Both patients were readily weaned from antihypertensive medications post-operatively, with complete resolution of hypertension within a few hours. Each pregnancy progressed normally to term.