Gesine Meyer

Real-Time Elastography for the Differentiation of Benign and Malignant Thyroid Nodules: A Meta-Analysis

BACKGROUND Work-up of thyroid nodules remains challenging. Fine-needle aspiration (FNA) has been shown to be the most cost-effective way to select patients for surgery with sensitivities of 54%–90% and specificities of 60%–96% for the detection of malignant lesions. Ultrasound-based real-time elastography (RTE) enables the determination of tissue elasticity and has shown promising results for the differentiation of thyroid nodules. A meta-analysis was performed to assess the overall performance of RTE for the differentiation of thyroid nodules. METHODS Literature databases were searched. The inclusion criteria for studies were the use of FNA cytology histopathology of surgical specimens as the diagnostic reference standard and assessment of sensitivity and specificity of RTE. The meta-analysis was performed using an inverse variance method and the Der Simonian and Laird Random effect estimator in case of established heterogeneity. RESULTS Eight studies that included a total of 639 thyroid nodules were analyzed. The overall mean sensitivity and specificity for the diagnosis of malignant thyroid nodules by RTE of the eight studies was 92% confidence interval 88–96 and 90% confidence interval 85–95, respectively. A significant heterogeneity was found for specificity of the different studies. CONCLUSIONS RTE has a high sensitivity and specificity in the evaluation of thyroid nodules. This technique might be useful in conjunction or even instead of FNA to select patients with thyroid nodules for surgery.

Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency

Primary adrenal insufficiency (PAI), or Addisons disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow‐up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21‐hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life‐threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow‐up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self‐adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addisons disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortiums investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow‐up.

Acoustic Radiation Force Impulse Imaging for Differentiation of Thyroid Nodules

Background Acoustic Radiation Force Impulse (ARFI)-Imaging is an ultrasound-based elastography method enabling quantitative measurement of tissue stiffness. The aim of the present study was to evaluate sensitivity and specificity of ARFI-imaging for differentiation of thyroid nodules and to compare it to the well evaluated qualitative real-time elastography (RTE). Methods ARFI-imaging involves the mechanical excitation of tissue using acoustic pulses to generate localized displacements resulting in shear-wave propagation which is tracked using correlation-based methods and recorded in m/s. Inclusion criteria were: nodules ≥5 mm, and cytological/histological assessment. All patients received conventional ultrasound, real-time elastography (RTE) and ARFI-imaging. Results One-hundred-fifty-eight nodules in 138 patients were available for analysis. One-hundred-thirty-seven nodules were benign on cytology/histology, and twenty-one nodules were malignant. The median velocity of ARFI-imaging in the healthy thyroid tissue, as well as in benign and malignant thyroid nodules was 1.76 m/s, 1.90 m/s, and 2.69 m/s, respectively. While no significant difference in median velocity was found between healthy thyroid tissue and benign thyroid nodules, a significant difference was found between malignant thyroid nodules on the one hand and healthy thyroid tissue (p = 0.0019) or benign thyroid nodules (p = 0.0039) on the other hand. No significant difference of diagnostic accuracy for the diagnosis of malignant thyroid nodules was found between RTE and ARFI-imaging (0.74 vs. 0.69, p = 0.54). The combination of RTE with ARFI did not improve diagnostic accuracy. Conclusions ARFI can be used as an additional tool in the diagnostic work up of thyroid nodules with high negative predictive value and comparable results to RTE.

Quality of Life in European Patients with Addison's Disease: Validity of the Disease-Specific Questionnaire AddiQoL

CONTEXT Patients with Addisons disease (AD) self-report impairment in specific dimensions on well-being questionnaires. An AD-specific quality-of-life questionnaire (AddiQoL) was developed to aid evaluation of patients. OBJECTIVE We aimed to translate and determine construct validity, reliability, and concurrent validity of the AddiQoL questionnaire. METHODS After translation, the final versions were tested in AD patients from Norway (n = 107), Sweden (n = 101), Italy (n = 165), Germany (n = 200), and Poland (n = 50). Construct validity was examined by exploratory factor analysis and Rasch analysis, aiming at unidimensionality and fit to the Rasch model. Reliability was determined by Cronbachs coefficient-α and Person separation index. Longitudinal reliability was tested by differential item functioning in stable patient subgroups. Concurrent validity was examined in Norwegian (n = 101) and Swedish (n = 107) patients. RESULTS Exploratory factor analysis and Rasch analysis identified six items with poor psychometric properties. The 30 remaining items fitted the Rasch model and proved unidimensional, supported by appropriate item and person fit residuals and a nonsignificant χ(2) probability. Crohnbachs α-coefficient 0.93 and Person separation index 0.86 indicate high reliability. Longitudinal reliability was excellent. Correlation with Short Form-36 and Psychological General Well-Being Index scores was high. A shorter subscale comprising eight items also proved valid and reliable. Testing of AddiQoL-30 in this large patient cohort showed significantly worse scores with increasing age and in women compared with men but no difference between patients with isolated AD and those with concomitant diseases. CONCLUSION The validation process resulted in a revised 30-item AddiQoL questionnaire and an eight-item AddiQoL short version with good psychometric properties and high reliability.

Nocturnal Hypoglycemia Identified by a Continuous Glucose Monitoring System in Patients with Primary Adrenal Insufficiency (Addison's Disease)

BACKGROUND Hypoglycemia can be a symptom in patients with Addisons disease. The common regimen of replacement therapy with oral glucocorticoids results in unphysiological low cortisol levels in the early morning, the time of highest insulin sensitivity. Therefore patients with Addisons disease are at risk for unrecognized and potentially severe nocturnal hypoglycemia also because of a disturbed counterregulatory function. Use of a continuous glucose monitoring system (CGMS) could help to adjust hydrocortisone treatment and to avoid nocturnal hypoglycemia in these patients. METHODS Thirteen patients with Addisons disease were screened for hypoglycemia wearing a CGMS for 3-5 days. RESULTS In one patient we identified a hypoglycemic episode at 3:45 a.m. with a blood glucose level of 46 mg/dL, clearly beneath the 95% tolerance interval of minimal glucose levels between 2 and 4 a.m. (53.84 mg/dL). After the hydrocortisone replacement scheme was changed, the minimum blood glucose level between 2 and 4 a.m. normalized to 87 mg/dL. CONCLUSIONS Continuous glucose monitoring can detect nocturnal hypoglycemia in patients with primary adrenal insufficiency and hence prevent in these patients an impaired quality of life and even serious adverse effects.

Increasing prevalence of Addison's disease in German females: health insurance data 2008–2012

OBJECTIVE Our objective was to investigate the epidemiology of autoimmune Addisons disease (AD) in Germany. DESIGN Routine data were analyzed from the Statutory Health Insurance (SHI) database of the Techniker Krankenkasse (TK) for an observation period from 01/01/2008 to 31/12/2012. The TK is one of the largest German health care insurance providers covering more than 10% of the German population. SUBJECTS AND METHODS Between 2008 and 2012, a total of 2477 diagnoses of primary adrenal failure were recorded in the SHI database. After exclusion of secondary, iatrogenic or other non-idiopathic forms and after adjustment for incomplete data sets, 1364 diagnoses of autoimmune-mediated AD remained. RESULTS The prevalence of AD in our cohort showed a steady increase from 82 per million in 2008 to 87 per million in 2012. On average, the prevalence rose about 1.8% per year, and due to a pronounced increase (2.7%) in females. The prevalence was lower in men (63-68 per million) than in women (96-108 per million). Autoimmune comorbidities were found in 46.5% of AD patients. Adrenal crises were documented with a frequency of 14-17/100 patient years. CONCLUSIONS These data provide a first epidemiological profile of this rare and perilous endocrine disease in Germany. Although the prevalence of AD appears lower than in the Scandinavian countries, the increasing figures in females over the last 5 years warrant further investigations. Furthermore, adrenal crises pose a considerable burden. Hereby, we can show that health insurance data provide a valuable tool for epidemiological studies in the absence of national registries.

Addison′s disease with polyglandular autoimmunity carries a more than 2.5‐fold risk for adrenal crises: German Health insurance data 2010‐2013

Adrenal crises are potentially life‐threatening complications in patients with adrenal insufficiency (AI). Our objective was to investigate the frequency of adrenal crises in different forms of AI.

High Frequency of Cytolytic 21-Hydroxylase–Specific CD8+ T Cells in Autoimmune Addison’s Disease Patients

The mechanisms behind destruction of the adrenal glands in autoimmune Addison’s disease remain unclear. Autoantibodies against steroid 21-hydroxylase, an intracellular key enzyme of the adrenal cortex, are found in >90% of patients, but these autoantibodies are not thought to mediate the disease. In this article, we demonstrate highly frequent 21-hydroxylase–specific T cells detectable in 20 patients with Addison’s disease. Using overlapping 18-aa peptides spanning the full length of 21-hydroxylase, we identified immunodominant CD8+ and CD4+ T cell responses in a large proportion of Addison’s patients both ex vivo and after in vitro culture of PBLs ≤20 y after diagnosis. In a large proportion of patients, CD8+ and CD4+ 21-hydroxylase–specific T cells were very abundant and detectable in ex vivo assays. HLA class I tetramer–guided isolation of 21-hydroxylase–specific CD8+ T cells showed their ability to lyse 21-hydroxylase–positive target cells, consistent with a potential mechanism for disease pathogenesis. These data indicate that strong CTL responses to 21-hydroxylase often occur in vivo, and that reactive CTLs have substantial proliferative and cytolytic potential. These results have implications for earlier diagnosis of adrenal failure and ultimately a potential target for therapeutic intervention and induction of immunity against adrenal cortex cancer.

CTLA-4 as a genetic determinant in autoimmune Addison's disease

In common with several other autoimmune diseases, autoimmune Addison’s disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3–DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28–CTLA-4–ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10–1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13–1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68–3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

Glukokortikoidinduzierte Insulinresistenz und Diabetes mellitus

Zusammenfassung.q Hintergrund: Glukokortikoide sind häufig verordnete Medikamente. Nahezu die Hälfte der langfristig mit diesen Pharmaka behandelten Patienten entwickelt eine Störung des Glucosestoffwechsels, die bei über 50% der Betroffenen auch nach Dosisreduktion oder Absetzen des Glukokortikoids bestehen bleibt.q Pathophysiologie: Glukokortikoide stören die insulinvermittelte Hemmung der hepatischen Glucosefreisetzung, vermindern die Glucoseutilisation im Muskelgewebe und führen zu einer Senkung der Insulinrezeptorbindungsaffinität. Der glukokortikoidinduzierte Diabetes mellitus ist damit pathophysiologisch einem demaskierten Typ-2-Diabetes gleichzusetzen. Neuere Untersuchungen lassen vermuten, dass eine Steigerung der endogenen Glukokortikoidproduktion insbesondere in Fettzellen auch eine Rolle in der Pathophysiologie des Typ-2-Diabetes spielen könnte.q Therapie: Patienten mit einem Glukokortikoiddiabetes weisen wie andere Diabetiker ein deutlich erhöhtes Risiko für arteriosklerotische und kardiovaskuläre Erkrankungen auf und sollten daher eine normnahe Stoffwechseleinstellung erhalten. Die Therapie des Glukokortikoiddiabetes entspricht prinzipiell der des Typ-2-Diabetes. In Frage kommen orale Antidiabetika – insbesondere Metformin und die Glitazone als Insulinsensitizer unter Beachtung der Kontraindikationen – oder eine Insulintherapie.Abstract.q Background: Glucocorticoids are frequently prescribed drugs. Nearly half of the patients treated with glucocorticoids over a longer period develop a deranged glucose metabolism. In about 50%, these disturbances persist despite reduction or even withdrawal of the drug.q Pathophysiology: Glucocorticoids antagonize the insulin-mediated inhibition of hepatic glucose release, decrease glucose utilisation in muscle, and reduce the binding affinity of insulin receptors. Therefore, glucocorticoid-induced diabetes mellitus is equivalent to unmasked type 2 diabetes. New studies presume that an increased endogenous production of glucocorticoids particularly in adipocytes could play a role in type 2 diabetes as well.q Therapy: Patients with glucocorticoid-induced diabetes bear, comparable to patients with other types of diabetes, a considerable risk of arteriosclerotic and cardiovascular diseases and should therefore receive an intensified treatment. Therapy of glucocorticoid-induced diabetes basically corresponds to that of type 2 diabetes. Applicable are oral antidiabetic drugs, particularly metformin and the glitazones as insulin sensitizers both requiring consideration of contraindications, or treatment with insulin.