Natural Autoimmunity to Selenoprotein P Impairs Selenium Transport in Hashimoto's Thyroiditis.

The essential trace element selenium (Se) is needed for the biosynthesis of selenocysteine-containing selenoproteins, including the secreted enzyme glutathione peroxidase 3 (GPX3) and the Se-transporter selenoprotein P (SELENOP). Both are found in blood and thyroid colloid, where they serve protective functions. Serum SELENOP derives mainly from hepatocytes, whereas the kidney contributes most serum GPX3. Studies using transgenic mice indicated that renal GPX3 biosynthesis depends on Se supply by hepatic SELENOP, which is produced in protein variants with varying Se contents. Low Se status is an established risk factor for autoimmune thyroid disease, and thyroid autoimmunity generates novel autoantigens. We hypothesized that natural autoantibodies to SELENOP are prevalent in thyroid patients, impair Se transport, and negatively affect GPX3 biosynthesis. Using a newly established quantitative immunoassay, SELENOP autoantibodies were particularly prevalent in Hashimoto's thyroiditis as compared with healthy control subjects (6.6% versus 0.3%). Serum samples rich in SELENOP autoantibodies displayed relatively high total Se and SELENOP concentrations in comparison with autoantibody-negative samples ([Se]; 85.3 vs. 77.1 µg/L, p = 0.0178, and [SELENOP]; 5.1 vs. 3.5 mg/L, p = 0.001), while GPX3 activity was low and correlated inversely to SELENOP autoantibody concentrations. In renal cells in culture, antibodies to SELENOP inhibited Se uptake. Our results indicate an impairment of SELENOP-dependent Se transport by natural SELENOP autoantibodies, suggesting that the characterization of health risk from Se deficiency may need to include autoimmunity to SELENOP as additional biomarker of Se status.

Extra-intracranial standard bypass in the elderly: perioperative risk, bypass patency and outcome.

BACKGROUND: Patients with chronic atherosclerotic vessel occlusion and cerebrovascular hemodynamic insufficiency may benefit from extra-intracranial (EC-IC) bypass surgery. Due to demographic changes, an increasing number of elderly patients presents with cerebrovascular hemodynamic insufficiency. So far, little data for EC-IC bypass surgery in elderly patients suffering occlusive cerebrovascular disease are available. We therefore designed a retrospective study to address the question whether EC-IC bypass is a safe and efficient treatment in a patient cohort ≥70 years. METHODS: 50 patients underwent EC-IC standard bypass surgery with translocation of the superficial temporal artery to an M2 segment of the medial cerebral artery. Criteria for bypass surgery were presence of symptomatic occlusive cerebrovascular disease of the anterior circulation and proof of a severely restricted or abrogated reserve capacity (detected by H2O-photon emission tomography or single photon emission computer tomography - before and after forced vessel dilatation by diamox). The incidence of perioperative neurological and surgical complications, bypass patency, bypass function and short-term outcome were retrospectively analyzed. RESULTS: The study cohort consisted of 16 patients ≥70 years (mean = 74.3 years, SE 1.3). It was compared to a cohort of 34 patients <70 years (mean = 61.2 years, SE 1.0). Both groups underwent EC-IC bypass surgery after careful preoperative work-up. Both patient groups did not differ significantly in gender, vascular pathology, previous history of diseases/comorbidity or clinical symptoms. The number of patients which underwent stenting or other endovascular treatments of the internal or common carotid artery prior to EC-IC bypass surgery was significantly higher in the group of patients ≥70 years (37.5 vs. 0%, p < 0.001). Perioperative stroke rate was 0% in both groups and mild morbidity occurred in 18.8 and 14.7%, respectively (p = 0.699). One 84-year-old female patient died due to perioperative endocarditis. Initial bypass patency was 93.8% in patients above the age of 70 years and 97.1% in the younger group (p = 0.542). Secondary occlusion rate was low in both groups (≥70 years: 0% vs. <70 years 3.7%). No new neurologic deficit occurred in patients with a patent bypass during the follow-up period (median 18 ± 13.1 months). Two patients with an initially occluded bypass and one with a secondary bypass occlusion suffered from new neurological symptoms. CONCLUSIONS: Our data show comparable safety and efficiency of EC-IC bypass surgery in patients under and above the age of 70 years due to a careful preoperative work-up and a strict indication for bypass surgery.

Selenium Status in Paediatric Patients with Neurodevelopmental Diseases.

Neurodevelopmental diseases are often associated with other comorbidities, especially inflammatory processes. The disease may affect the trace element (TE) status, which in turn may affect disease severity and progression. Selenium (Se) is an essential TE required for the biosynthesis of selenoproteins including the transporter selenoprotein P (SELENOP) and extracellular glutathione peroxidase (GPX3). SELENOP deficiency in transgenic mice resulted in a Se status-dependent phenotype characterized by impaired growth and disturbed neuronal development, with epileptic seizures on a Se-deficient diet. Therefore, we hypothesized that Se and SELENOP deficiencies may be prevalent in paediatric patients with a neurodevelopmental disease. In an exploratory cross-sectional study, serum samples from children with neurodevelopmental diseases (n = 147) were analysed for total serum Se, copper (Cu), and zinc (Zn) concentrations as well as for the TE biomarkers SELENOP, ceruloplasmin (CP), and GPX3 activity. Children with epilepsy displayed elevated Cu and Zn concentrations but no dysregulation of serum Se status. Significantly reduced SELENOP concentrations were found in association with intellectual disability (mean ± SD (standard deviation); 3.9 ± 0.9 mg/L vs. 4.4 ± 1.2 mg/L, p = 0.015). A particularly low GPX3 activity (mean ± SD; 172.4 ± 36.5 vs. 192.6 ± 46.8 U/L, p = 0.012) was observed in phacomatoses. Autoantibodies to SELENOP, known to impair Se transport, were not detected in any of the children. In conclusion, there was no general association between Se deficiency and epilepsy in this observational analysis, which does not exclude its relevance to individual cases. Sufficiently high SELENOP concentrations seem to be of relevance to the support of normal mental development. Decreased GPX3 activity in phacomatoses may be relevant to the characteristic skin lesions and merits further analysis. Longitudinal studies are needed to determine whether the observed differences are relevant to disease progression and whether correcting a diagnosed TE deficiency may confer health benefits to affected children.

Natural Autoimmunity to the Thyroid Hormone Monocarboxylate Transporters MCT8 and MCT10.

The monocarboxylate transporters 8 (MCT8) and 10 (MCT10) are important for thyroid hormone (TH) uptake and signaling. Reduced TH activity is associated with impaired development, weight gain and discomfort. We hypothesized that autoantibodies (aAb) to MCT8 or MCT10 are prevalent in thyroid disease and obesity. Analytical tests for MCT8-aAb and MCT10-aAb were developed and characterized with commercial antiserum. Serum samples from healthy controls, thyroid patients and young overweight subjects were analyzed, and prevalence of the aAb was compared. MCT8-aAb were additionally tested for biological effects on thyroid hormone uptake in cell culture. Positive MCT8-aAb and MCT10-aAb were detected in all three clinical cohorts analyzed. MCT8-aAb were most prevalent in thyroid patients (11.9%) as compared to healthy controls (3.8%) and overweight adolescents (4.2%). MCT8-aAb positive serum reduced T4 uptake in cell culture in comparison to MCT8-aAb negative control serum. Prevalence of MCT10-aAb was highest in the group of thyroid patients as compared to healthy subjects or overweight adolescents (9.0% versus 4.5% and 6.3%, respectively). We conclude that MCT8 and MCT10 represent autoantigens in humans, and that MCT8-aAb may interfere with regular TH uptake and signaling. The increased prevalence of MCT8-aAb and MCT10-aAb in thyroid disease suggests that their presence may be of pathophysiological relevance. This hypothesis deserves an analysis in large prospective studies.

Cross-sectional analysis of trace element status in thyroid disease.

BACKGROUND: The synthesis of thyroid hormone depends on a set of trace elements, most importantly selenium and iodine. The dietary supply with certain micronutrients is limited in many areas of the world, including central Europe and large parts of Asia and Africa. Moreover, both thyroid disease risk and therapy effects are modulated by trace element supply and status. OBJECTIVE: Assessment of trace element status in thyroid patients in a European metropolis. MATERIAL AND METHODS: Adult patients visiting a medical praxis in Berlin, Germany, were enrolled into a cross-sectional analysis, and serum samples were obtained from thyroid patients (n = 323) with different conditions including goitre, hypothyroidism, malignancy or autoimmune thyroid disease. Trace elements (iodine, selenium, copper and zinc) were assessed by ICP-MS/MS or total reflection X-ray analysis, along with two protein biomarkers of selenium status (selenoprotein P, glutathione peroxidase), and compared to the clinical phenotype. RESULTS: The patients displayed relatively low serum zinc and selenium concentrations as compared to a set (n = 200) of healthy subjects (zinc; 1025+/-233 vs. 1068+/-230 µg/L, p < 0.01, selenium; 76.9+/18.8 vs. 85.1+/-17.4 µg/L, p < 0.0001). A high fraction of patients (37.5%) was classified as selenium-deficient (serum selenium concentrations <70 µg/L), in particular the patients with thyroid malignancy (59%). Serum copper was not different between the groups, and total serum iodine concentrations were unrelated to thyroid disease. Explorative statistical analyses yielded no significant interactions between the trace elements and disease parameters, except for free thyroxine inversely correlating to the copper/selenium ratio. CONCLUSIONS: In adult thyroid patients, there is no relation of circulating copper, iodine, selenium or zinc concentrations to thyroid hormone. However, a large fraction of German thyroid patients displays a considerable selenium deficit, known to constitute a disease risk potentially impairing convalescence and aggravating autoimmune disease processes. It appears advisable to testing thyroid patients for selenium deficiency, and once diagnosed, an increased supply via dietary counselling or active supplementation should be considered.

Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease.

OBJECTIVE: Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral sodium-iodide-symporter (NIS (SLC5A5)) and the apical anion exchanger pendrin (PDS (SLC26A4)). Both transmembrane proteins have been described as autoantigens in thyroid disease, yet the reports on autoantibody (aAb) prevalence and diagnostic usefulness are conflicting. Reasons for the inconclusive findings may be small study groups and principle differences in the technologies used. DESIGN: We decided to re-evaluate this important issue by establishing novel non-radioactive tests using full-length antigens and comparable protocols, and analyzing a large cohort of thyroid patients (n = 323) and control samples (n = 400). METHODS: NIS and PDS were recombinantly expressed as fusion protein with firefly luciferase (Luc). Stably transfected HEK293 cells were used as reproducible source of the autoantigens. RESULTS: Recombinant NIS-Luc showed iodide transport activity, indicating successful expression and correct processing. Commercial antibodies yielded dose-dependent responses in the newly established assays. Reproducibility of assay signals from patient sera was verified with respect to linearity, stability and absence of matrix effects. Prevalence of PDS-aAb was similar in thyroid patients and controls (7.7% vs 5.0%). NIS-aAb were more prevalent in patients than controls (7.7% vs 1.8%), especially in Graves' Disease (12.3%). Neither NIS-aAb nor PDS-aAb concentrations were related to TPO-aAb or TSH-receptor-aAb concentrations, or to serum zinc or selenium status. CONCLUSIONS: Our data highlight a potential relevance of autoimmunity against NIS for thyroid disease, whereas an assessment of PDS-aAb in thyroid patients seems not to be of diagnostic value (yet).

Influence of attenuation correction by integrated low-dose CT on somatostatin receptor SPECT.

AIM: Somatostatin receptor scintigraphy (SRS) is well-established in neuroendocrine tumour (NET) imaging. This study evaluated the impact of attenuation correction (AC) on SRS SPECT data in patients examined by SPECT-CT. METHODS: Planar scintigraphy and SPECT-CT of 17 patients (10 men, seven women; age, 40-74 years; mean, 62 years) suffering from NET were included. For the visual assessment of AC, the intensity and contrast of foci classified as pathological were rated in both the non-attenuation corrected (NAC) and the attenuation corrected (AC) SPECT images using a 5-point score. The change in signal intensity after AC was semiquantified two-fold for each focus in both SPECT(AC) and SPECT(NAC): firstly by using tumour-to-background (TB) ratios (defined as T(max)/B(mean)) for the determination of a TB(AC)/TB(NAC) ratio. Secondly, by a T(max,AC)/T(max,NAC) ratio. Both ratios were correlated to the focus depth. RESULTS: A total of 46 pathological foci were found. Focus contrast and intensity significantly increased in 14/46 foci (30%) after AC (mean, 3.7-4.0) in the visual analysis (P<0.001). While TB ratios increased only in 24/46 foci after AC and no correlation between the T(BAC)/T(BNAC) ratio and focus depth (r=0.027; P=0.856) was found, T(max) was higher after AC in all foci and the T(max,AC)/T(max,NAC) ratio showed the expected correlation to focus depth (r=0.650; P<0.01), indicating the superiority of the Tmax approach for the demonstration of the effects of attenuation correction on focal uptake. CONCLUSION: Attenuation correction of SRS SPECT data by SPECT-CT results in visually more clearly contrasted foci. Moreover, as focus intensity increases, especially in the more centrally localised foci, CT-based AC has a potential to further improve the sensitivity of SRS SPECT.

Attenuation correction of somatostatin receptor SPECT by integrated low-dose CT: is there an impact on sensitivity?

AIM: Somatostatin receptor scintigraphy (SRS) is an established imaging modality for neuroendocrine tumors (NET). Additional single photon emission computed tomography (SPECT-CT) not only permits image fusion but also attenuation correction (AC) of SPECT data. This study evaluated whether attenuation corrected SPECT-images (SPECT[AC]) are more sensitive than nonattenuation corrected SPECT-reconstructions (SPECT[NAC]) for the detection of NET lesions. METHODS: The imaging data (planar In-111-octreotide scintigraphy and SPECT-CT) of 50 consecutive patients (28 male; 22 female; age, 34-80; mean, 65 years) with NET were included in this retrospective analysis. SPECT data were reconstructed with and without integrated CT-based AC and then analyzed by 2 experienced readers for the presence of pathologic uptake in a blinded consensus reading. Fused SPECT-CT, contemporary CT/MRI, and clinical as well as imaging follow-up served as a reference standard. All foci were rated in both the SPECT(NAC)- and SPECT(AC)-reconstructions for intensity and contrast using a 6-point-score ("0 = no uptake/no delineation from surrounding tissue" to "5 = very high uptake/very strong delineation from surrounding tissue"). The scores were analyzed in a 6 x 6 contingency table using the McNemar Bowker test. RESULTS: A total of 222 pathologic foci were detected by SPECT(NAC) and 227 foci by SPECT(AC), respectively. In 67 of 227 foci (29.5%), focus intensity/contrast increased after AC, whereas only 5 foci showed a decrease (P < 0.001). Sensitivity increased by 2.2% (P = 0.025; 95% CI: 0.02%-4.1%) as 5 foci were detected only by SPECT(AC). However, as these 3 patients were already diagnosed with systemic disease, there was no influence on the therapeutic strategy chosen. CONCLUSION: Attenuation correction of somatostatin receptor scintigraphy-SPECT significantly improves focus visualization and, albeit slightly, also significantly increases sensitivity.