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OBJECTIVE: Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. DESIGN: Cross-sectional study. METHODS: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250â µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. RESULTS: Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60â min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively). CONCLUSIONS: We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small.
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Enfermedad de Addison , Enfermedades Cardiovasculares , Humanos , Masculino , Femenino , Enfermedad de Addison/complicaciones , Estudios Transversales , Calidad de Vida , Leptina , Glucocorticoides , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/complicaciones , Inflamación , Cosintropina , Biomarcadores , Proteínas de Neoplasias , Proteínas de la Matriz ExtracelularRESUMEN
PURPOSE: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison's disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. METHODS: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). RESULTS: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. CONCLUSION: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.
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CONTEXT: Autoimmune thyroid disease is the most common endocrine comorbidity in autoimmune Addison disease (AAD), but detailed investigations of prevalence and clinical course are lacking. OBJECTIVE: This work aimed to provide comprehensive epidemiological and clinical data on autoimmune thyroid disorders in AAD. METHODS: A nationwide registry-based study including 442 patients with AAD and autoimmune thyroid disease were identified through the Norwegian National Registry of Autoimmune Diseases. RESULTS: Of 912 registered AAD patients, 442 (48%) were diagnosed with autoimmune thyroid disease. A total of 380 (42%) had autoimmune hypothyroidism. Of the 203 with available thyroid function tests at time of diagnosis, 20% had overt hypothyroidism, 73% had subclinical hypothyroidism, and 7% had thyroid levels in the normal range. Negative thyroid peroxidase antibodies was found in 32%. Ninety-eight percent were treated with levothyroxine, 5% with combination therapy with liothyronine or thyroid extracts, and 1% were observed without treatment. Seventy-eight patients (9%) were diagnosed with Graves disease (GD), of whom 16 (21%) were diagnosed with autoimmune hypothyroidism either before onset or after remission of GD. At the end of follow-up, 33% had normal thyroid hormone levels without antithyroid-drugs or levothyroxine treatment. The remaining had either active disease (5%), had undergone ablative treatment (41%), or had developed autoimmune hypothyroidism (21%). CONCLUSION: The true prevalence of hypothyroidism in AAD is lower than reported in the current literature. Careful consideration of the indication to start thyroxin therapy is warranted. Long-term remission rates in GD patients with AAD are comparable to recent reports on long-term follow-up of patients without AAD.
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Enfermedad de Addison , Enfermedad de Graves , Enfermedad de Hashimoto , Hipotiroidismo , Enfermedad de Addison/complicaciones , Enfermedad de Addison/tratamiento farmacológico , Enfermedad de Addison/epidemiología , Enfermedad de Graves/complicaciones , Enfermedad de Graves/tratamiento farmacológico , Enfermedad de Graves/epidemiología , Enfermedad de Hashimoto/tratamiento farmacológico , Humanos , Hipotiroidismo/complicaciones , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/epidemiología , Hormonas Tiroideas/uso terapéutico , Tiroiditis Autoinmune , Tiroxina/uso terapéuticoRESUMEN
CONTEXT: Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. OBJECTIVE: To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. DESIGN: Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone afterâ >â 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography-tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. RESULTS: Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (nâ =â 33; Pâ <â 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; Pâ <â 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; Pâ <â 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; Pâ <â 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; Pâ <â 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (râ =â 0.989; Pâ <â 0.001) and plasma adrenocorticotropic hormone (ACTH; râ =â -0.487; Pâ <â 0.001). CONCLUSION: In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life.
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Enfermedad de Addison/sangre , Corticoesteroides/sangre , Adulto , Cosintropina/sangre , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Subclinical hyperthyroidism is a clinical condition with a laboratory diagnosis defined as a suppressed below the normal range TSH level and normal free thyroxine and triiodothyronine levels. The condition is frequently recognized but its long-term clinical consequences are constantly debated. There is little good evidence available to guide the management of patients with subclinical hyperthyroidism. This review summarizes current state of knowledge on the prevalence, aetiology, clinical consequences and treatment of subclinical hypertyroidism.
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Hipertiroidismo/diagnóstico , Hipertiroidismo/terapia , Enfermedades Óseas/epidemiología , Enfermedades Cardiovasculares/epidemiología , Causalidad , Comorbilidad , Progresión de la Enfermedad , Humanos , Hipertiroidismo/epidemiología , Trastornos Mentales/epidemiologíaRESUMEN
INTRODUCTION: Chronic inflammation in asthmatic airways leads to bronchial hyper-responsiveness (BHR) and the development of structural changes. Important features of remodeling include the formation of subepithelial fibrosis due to increased collagen deposition in the reticular basement membrane. Transforming growth factor (TGF)-beta might be a central mediator of tissue fibrosis and remodeling. MATERIALS AND METHODS: Immunohistochemistry was used to measure collagen III deposition and TGF-beta(1) expression in biopsies from patients with long-standing asthma treated with inhaled corticosteroids, patients with recently diagnosed asthma, and control subjects. Computer-assisted image analysis was used to evaluate total basement membrane (TBM) thickness. RESULTS: Asthmatics, particularly those with long-standing asthma, had thicker TBMs than healthy subjects. Collagen III deposition was comparable in the studied groups. BHR was not correlated with features of mucosal inflammation and was lower in steroid-treated patients with long-standing asthma than in subjects with newly diagnosed asthma untreated with steroids. Epithelial TGF-beta(1) expression negatively correlated with collagen III deposition and TBM thickness. CONCLUSIONS: The study showed that TBM thickness, but not collagen III deposition, could be a differentiating marker of asthmatics of different disease duration and treatment. The lack of correlation between BHR and features of mucosal inflammation suggests the complexity of BHR development. Corticosteroids can reduce BHR in asthmatics, but it seems to be less effective in reducing subepithelial fibrosis. The role of epithelial TGF-beta(1) needs to be further investigated since the possibility that it plays a protective and anti-inflammatory role in asthmatic airways cannot be excluded.
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Asma/metabolismo , Bronquios/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Adulto , Anciano , Colágeno/metabolismo , Femenino , Fibrosis/patología , Humanos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica/métodos , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Modelos BiológicosRESUMEN
Asthma is a chronic inflammatory disease of the airways. Structural alteration of the airways and lung parenchyma, "remodeling", is a recognized feature of chronic asthma and a cause of irreversible airway obstruction. Airway and lung remodeling in asthma involves subepithelial fibrosis, but also alterations of bronchial epithelium, airway smooth muscle cells, myofibroblasts, extracellular matrix, mucous glands, blood vessels and nerves. Defining of morphological changes and correlating them with clinical features of the disease has been a major focus of research over the past decade. The results of these studies are often contradictory and there is still little understanding of the mechanisms underlying lung remodeling in asthma.