scholarly journals Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison’s Disease

2021 ◽  
Author(s):  
Åse Bjorvatn Sævik ◽  
Anette B Wolff ◽  
Sigridur Björnsdottir ◽  
Katerina Simunkova ◽  
Martha Schei Hynne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Addison’S Disease ◽  
Serum Cortisol ◽  
Normal Serum ◽  
Addison's Disease ◽  
Rt Pcr ◽  
Expression Levels ◽  
Morning Cortisol ◽  
Cortisol Levels ◽  
Transcriptional Biomarkers

Abstract Background No reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD), leading to overtreatment with alarming and persistent side-effects or undertreatment, which could be fatal. Objective To explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD. Methods Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In three of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and two, four, and six hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. Results Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. Conclusions We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

scholarly journals Gene Expression to Guide Glucocorticoid Replacement in Autoimmune Addison’s Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A83-A83
Author(s):  
Åse Bjorvatn Sævik ◽  
Anette Wolff ◽  
Sigridur Björnsdottir ◽  
Katerina Simunkova ◽  
Martha S Hynne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Addison’S Disease ◽  
Serum Cortisol ◽  
Normal Serum ◽  
Addison's Disease ◽  
Expression Levels ◽  
Morning Cortisol ◽  
Cortisol Levels ◽  
Compare Gene Expression ◽  
Gene Expression Levels

Abstract Objective: Deciding the optimal doses of glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD) is impeded by the lack of reliable biomarkers. This frequently results in over-treatment, with alarming and persistent side-effects, or under-replacement, which could be fatal. There is a need to think new in the quest for robust biomarkers to optimize GC replacement in AAD at an individual level. Aim: We aimed to identify genes that are consistently up- or down-regulated in patients with AAD in response to different GC replacement doses. This information can be used to establish novel biomarkers to guide GC treatment in AAD. Methods: Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. To verify the results, we performed real-time PCR to compare gene expression levels of three of the highly differentially expressed genes (FKBP5, MMP9, and DSIPI) to compare gene expression levels before and two, four, and six hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. Results: Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. Conclusions: We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

scholarly journals Adrenal Steroidogenesis after B Lymphocyte Depletion Therapy in New-Onset Addison's Disease

2012 ◽  
Vol 97 (10) ◽  
pp. E1927-E1932 ◽  
Author(s):  
Simon H. S. Pearce ◽  
Anna L. Mitchell ◽  
Stuart Bennett ◽  
Phil King ◽  
Sukesh Chandran ◽  
...  
Keyword(s):  
B Lymphocyte ◽  
Addison’S Disease ◽  
Serum Cortisol ◽  
Adrenal Crisis ◽  
Addison's Disease ◽  
Adrenal Failure ◽  
Lymphocyte Depletion ◽  
Adrenal Steroidogenesis ◽  
Cortisol Levels ◽  
New Onset

Abstract Context: A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. Objective: The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis. Design and Intervention: This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. Patients and Main Outcome Measures: Six patients (aged 17–47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. Results: Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. Conclusion: New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted.

scholarly journals Ambient air pollutants are associated with morning serum cortisol in overweight and obese Latino youth in Los Angeles

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
C. M. Toledo-Corral ◽  
T. L. Alderete ◽  
M. M. Herting ◽  
R. Habre ◽  
A. K. Peterson ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Air Pollutants ◽  
Latino Youth ◽  
Serum Cortisol ◽  
Ambient Air ◽  
Pubertal Status ◽  
Ambient Air Pollutants ◽  
Morning Cortisol ◽  
Morning Serum Cortisol ◽  
Cortisol Levels

Abstract Background Hypothalamic-pituitary-adrenal (HPA)-axis dysfunction has been associated with a variety of mental health and cardio-metabolic disorders. While causal models of HPA-axis dysregulation have been largely focused on either pre-existing health conditions or psychosocial stress factors, recent evidence suggests a possible role for central nervous system activation via air pollutants, such as nitrogen dioxide (NO2), ozone (O3) and particulate matter (PM). Therefore, in an observational study of Latino youth, we investigated if monthly ambient NO2, O3, and PM with aerodynamic diameter ≤ 2.5 (PM2.5) exposure were associated with morning serum cortisol levels. Methods In this cross-sectional study, morning serum cortisol level was assessed after a supervised overnight fast in 203 overweight and obese Latino children and adolescents (female/male: 88/115; mean age: 11.1 ± 1.7 years; pre-pubertal/pubertal/post-pubertal: 85/101/17; BMI z-score: 2.1 ± 0.4). Cumulative concentrations of NO2, O3 and PM2.5 were spatially interpolated at the residential addresses based on measurements from community monitors up to 12 months prior to testing. Single and multi-pollutant linear effects models were used to test the cumulative monthly lag effects of NO2, O3, and PM2.5 on morning serum cortisol levels after adjusting for age, sex, seasonality, social position, pubertal status, and body fat percent by DEXA. Results Single and multi-pollutant models showed that higher O3 exposure (derived from maximum 8-h exposure windows) in the prior 1–7 months was associated with higher serum morning cortisol (p < 0.05) and longer term PM2.5 exposure (4–10 months) was associated with lower serum morning cortisol levels (p < 0.05). Stratification by pubertal status showed associations in pre-pubertal children compared to pubertal and post-pubertal children. Single, but not multi-pollutant, models showed that higher NO2 over the 4–10 month exposure period associated with lower morning serum cortisol (p < 0.05). Conclusions Chronic ambient NO2, O3 and PM2.5 differentially associate with HPA-axis dysfunction, a mechanism that may serve as an explanatory pathway in the relationship between ambient air pollution and metabolic health of youth living in polluted urban environments. Further research that uncovers how ambient air pollutants may differentially contribute to HPA-axis dysfunction are warranted.

scholarly journals A high-sensitivity test in the assessment of adrenocortical insufficiency: 10 microg vs 250 microg cosyntropin dose assessment of adrenocortical insufficiency

1998 ◽  
Vol 159 (2) ◽  
pp. 275-280 ◽  
Author(s):  
JG Gonzalez-Gonzalez ◽  
NE De la Garza-Hernandez ◽  
LG Mancillas-Adame ◽  
J Montes-Villarreal ◽  
JZ Villarreal-Perez
Keyword(s):  
Healthy Subjects ◽  
Low Dose ◽  
Standard Dose ◽  
Addison’S Disease ◽  
High Sensitivity ◽  
Serum Cortisol ◽  
Dose Assessment ◽  
Addison's Disease ◽  
Acth Test ◽  
Adrenocortical Insufficiency

The short cosyntropin (synthetic ACTH) test is recognized as the best screening manoeuvre in the assessment of adrenocortical insufficiency. Recent data, however, suggest that i.v. administration of 250 microg cosyntropin could be a pharmacological rather than a physiological stimulus, losing sensitivity for detecting adrenocortical failure. Our objective was to compare 10 vs 250 microg cosyntropin in order to find differences in serum cortisol peaks in healthy individuals, the adrenocortical response in a variety of hypothalamic-pituitary-adrenal axis disorders and the highest sensitivity and specificity serum cortisol cut-off point values. The subjects were 83 healthy people and 37 patients, the latter having Addison's disease (11), pituitary adenomas (7), Sheehan's syndrome (9) and recent use of glucocorticoid therapy (10). Forty-six healthy subjects and all patients underwent low- and standard-dose cosyntropin testing. In addition, 37 controls underwent the low-dose test. On comparing low- and standard-dose cosyntropin testing in healthy subjects there were no statistical differences in baseline and peaks of serum cortisol. In the group of patients, 2 out of 11 cases of Addison's disease showed normal cortisol criterion values during the standard test but abnormal during the low-dose test. In our group of patients and controls, the statistical analysis displayed a better sensitivity of the low-dose vs standard-dose ACTH test at 30 and 60 min. In conclusion, these results suggest that the use of 10 microg rather than 250 microg cosyntropin i.v. in the assessment of suspicious adrenocortical dysfunction gives better results.

scholarly journals Monitoring gene expression changes in bovine oviduct epithelial cells during the oestrous cycle

2004 ◽  
Vol 32 (2) ◽  
pp. 449-466 ◽  
Author(s):  
S Bauersachs ◽  
S Rehfeld ◽  
SE Ulbrich ◽  
S Mallok ◽  
K Prelle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Expression Profiles ◽  
Cdna Array ◽  
Oestrous Cycle ◽  
Cdna Clones ◽  
Rt Pcr ◽  
Expression Levels ◽  
Starting Point ◽  
Oviduct Epithelial Cells

The oviduct epithelium undergoes marked morphological and functional changes during the oestrous cycle. To study these changes at the level of the transcriptome we did a systematic gene expression analysis of bovine oviduct epithelial cells at oestrus and dioestrus using a combination of subtracted cDNA libraries and cDNA array hybridisation. A total of 3072 cDNA clones of two subtracted libraries were analysed by array hybridisation with cDNA probes derived from six cyclic heifers, three of them slaughtered at oestrus and three at dioestrus. Sequencing of cDNAs showing significant differences in their expression levels revealed 77 different cDNAs. Thirty-seven were expressed at a higher level at oestrus, for the other 40 genes expression levels were higher at dioestrus. The identified genes represented a variety of functional classes. During oestrus especially genes involved in the regulation of protein secretion and protein modification, and mRNAs of secreted proteins, were up-regulated, whereas during dioestrus particularly transcripts of genes involved in transcription regulation showed a slight up-regulation. The concentrations of seven selected transcripts were quantified by real-time RT-PCR to validate the cDNA array hybridisation data. For all seven transcripts, RT-PCR results were in excellent correlation (r>0.92) with the results obtained by array hybridisation. Our study is the first to analyse changes in gene expression profiles of bovine oviduct epithelial cells during different stages of the oestrous cycle, providing a starting point for the clarification of the key transcriptome changes in these cells.

Atypical Addison's disease in the dog: a retrospective survey of 14 cases

1996 ◽  
Vol 32 (2) ◽  
pp. 159-163 ◽  
Author(s):  
D Sadek ◽  
M Schaer
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Clinical Signs ◽  
Addison’S Disease ◽  
Normal Serum ◽  
Definitive Diagnosis ◽  
Addison's Disease ◽  
Serum Electrolyte ◽  
Acth Stimulation ◽  
Retrospective Survey ◽  
Adrenocortical Response

Fourteen dogs diagnosed with Addison's disease and having atypical serum electrolyte levels are described. Seventy-eight percent were female, and most showed signs of inappetence, weakness, or vomiting. Ninety-three percent of the cases had either hyponatremia without hyperkalemia or normal serum electrolyte concentrations. Hemogram features were variable and were not useful in suggesting a diagnosis of hypoadrenocorticism. The results of this study show that normal or mild serum electrolyte changes in a dog with clinical signs compatible with Addison's disease should not exclude this diagnosis from consideration. Definitive diagnosis depends on the demonstration of inadequate adrenocortical response to adrenocorticotropic hormone (ACTH) stimulation.

Identification of Molecular Risk Score in Advanced Hodgkin Lymphoma: Integrating Tumor and Microenvironment Signatures.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3660-3660
Author(s):  
Beatriz Sánchez-Espiridión ◽  
Carlos Montalbán ◽  
Mónica García-Cosio ◽  
Jose García-Laraña ◽  
Javier Menarguez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Treatment Response ◽  
Hodgkin Lymphoma ◽  
Risk Score ◽  
Molecular Techniques ◽  
Gene Set Enrichment Analysis ◽  
Transcriptional Analysis ◽  
Rank Statistic ◽  
Rt Pcr ◽  
Expression Levels

Abstract Abstract 3660 Poster Board III-596 Introduction Despite the major advances in the treatment of classical Hodgkin Lymphoma (cHL) patients, around 30% to 40% of cases in advanced stages may relapse or die as result of the disease. Current predictive systems, based on clinical and analytical parameters, fail to identify accurately this significant fraction of patients with short failure-free survival (FFS). Transcriptional analysis has identified genes and pathways associated with clinical failure, but the biological relevance and clinical applicability of these data await further development. Robust molecular techniques for the identification of biological processes associated with treatment response are necessary for developing new predictive tools. Patients and Methods We used a multistep approach to design a quantitative RT-PCR-based assay to be applied to routine formalin-fixed, paraffin-embedded samples (FFPEs), integrating genes known to be expressed either by the tumor cells and their reactive microenvironment, and related with clinical response to adriamycin-based chemotherapy. First, analysis of 29 patient samples allowed the identification of gene expression signatures related to treatment response and outcome and the design of an initial RT-PCR assay tested in 52 patient samples. This initial model included 60 genes from pathways related to cHL outcome that had been previously identified using Gene Set Enrichment Analysis (GSEA). Second, we selected the best candidate genes from the initial assay based on amplification efficiency, biological significance and treatment response correlation to set up a novel assay of 30 genes that was applied to a large series of 282 samples that were randomly split and assigned to either estimation (194) or validation series (88). The results of this assay were used to design an algorithm, based on the expression levels of the best predictive genes grouped in pathways, and a molecular risk score was calculated for each tumor sample. Results Adequate RT-PCR profiles were obtained in 264 of 282 (93,6%) cases. Normalized expression levels (DCt) of individual genes vary considerably among samples. The strongest predictor genes were selected and included in a multivariate 10-gene model integrating four gene expression pathway signatures, termed CellCycle, Apoptosis, NF-KB and Monocyte, which are able to predict treatment response with an overall accuracy of 68.5% and 73.4% in the estimation and validation sets, respectively. Patients were stratified by their molecular risk score and predicted probabilities identified two distinct risk groups associated with clinical outcome in the estimation (5-year FFS probabilities 75.6% vs. 45.9%, log rank statistic p≈0.000) and validation sets (5-year FFS probabilities 71.4% vs. 43.5%, log rank statistic p<0.004). Moreover, this biological model is independent of and complementary to the conventional International Prognostic Score using multivariate Cox proportional hazards analysis. Conclusions We have developed a molecular risk algorithm that includes genes expressed by tumoral cells and their reactive microenvironment. This makes it possible to classify advanced cHL patients with different risk of treatment failure using a method that could be applied to routinely prepared tumor blocks. These results could pave the way for more individualized and risk-adapted treatment strategies of cHL patients, enabling subsets of patients to be identified who might benefit from alternative approaches Disclosures: No relevant conflicts of interest to declare.

Mineralocorticoid Before Glucocorticoid Deficiency in a Dog with Primary Hypoadrenocorticism and Hypothyroidism

2013 ◽  
Vol 49 (1) ◽  
pp. 54-57 ◽  
Author(s):  
Kathryn M. McGonigle ◽  
John F. Randolph ◽  
Sharon A. Center ◽  
Richard E. Goldstein
Keyword(s):  
Clinical Signs ◽  
Addison’S Disease ◽  
Serum Cortisol ◽  
Primary Hypothyroidism ◽  
Addison's Disease ◽  
Acth Stimulation Test ◽  
Acth Stimulation ◽  
Clinical Illness ◽  
Glucocorticoid Deficiency ◽  
Electrolyte Abnormalities

A dog with an unexpected presentation of primary hypoadrenocorticism was evaluated for clinical signs and electrolyte abnormalities characteristic of Addison’s disease. Although the initial adrenocorticotropic hormone (ACTH) stimulation test documented serum cortisol concentrations within the reference range, subsequent assessments confirmed hypoaldosteronism. Mineralocorticoid replacement promptly normalized electrolytes and transiently improved clinical illness. Six weeks after initial ACTH stimulation testing, the dog became glucocorticoid deficient. Concurrent primary hypothyroidism was also documented. Hypoaldosteronism preceding hypocortisolemia is a unique presentation of canine Addison’s disease.

SUBCLINICAL HYPOTHYROIDISM IN ADDISON'S DISEASE

1979 ◽  
Vol 91 (4) ◽  
pp. 674-679 ◽  
Author(s):  
Jens Faber ◽  
Dorte Cohn ◽  
Carsten Kirkegaard ◽  
Morten Christy ◽  
Kaj Siersbæk-Nielsen ◽  
...  
Keyword(s):  
Addison’S Disease ◽  
Mean Value ◽  
Normal Serum ◽  
Control Group ◽  
Addison's Disease ◽  
Normal Range ◽  
Microsomal Antibody ◽  
The Mean ◽  
Thyroid Microsomal Antibodies ◽  
Serum Tsh

ABSTRACT Fourteen patients with Idiopatic Addison's disease (IAD) were studied in order to detect a possible subclinical hypothyroid state. All were clinically euthyroid with normal serum thyroxine (T4) and serum 3,5′,3′-triiodothyronine (T3). Eleven had circulating thyroid microsomal antibodies in blood. The mean basal serum TSH was significantly higher than that of the control group but only three patients had values above the upper normal range. The mean value of serum T4 was decreased as compared to that of the normal persons, while serum 3,3′,5′-triiodothyronine was elevated. 7.5 mU bovine thyrotrophin per kilogram body weight injected intravenously caused a rise in serum T3 not different from the response in normals. However, as well increasing serum TSH as increasing microsomal antibody titer correlated significantly to decreasing thyroidal release of T3. Our results suggest that clinically euthyroid patients suffering from IAD might have a beginning thyroidal insufficiency because of a progressive immunological damage of the thyroid.

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