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Lancet Diabetes Endocrinol ; 8(9): 773-781, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32711725


BACKGROUND: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. METHODS: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. FINDINGS: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0). INTERPRETATION: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. FUNDING: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/urina , Metabolômica/métodos , Esteroides/urina , Neoplasias das Glândulas Suprarrenais/diagnóstico , Adulto , Idoso , Diagnóstico Diferencial , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
J Clin Endocrinol Metab ; 103(12): 4553-4560, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137397


Context: Autonomous cortisol secretion (ACS) can be unilateral or bilateral irrespective of the presence of an adrenal tumor. A reliable method to distinguish between unilateral and bilateral ACS is lacking. Objective: Evaluate the use of adrenal venous sampling (AVS) to distinguish between unilateral and bilateral ACS. Design and Methods: This was a prospective study of AVS in patients with adrenal tumors who received a diagnosis of ACS or adrenal Cushing syndrome (CS). Unilateral secretion was defined as >2.3-fold difference in cortisol levels between the two adrenal veins. Metanephrine levels were used to ascertain correct catheter position. Results were correlated with findings on CT and iodine-131-cholesterol scintigraphy. Results: Thirty-nine patients underwent AVS; there were no complications. The procedure was inconclusive in six patients and repeated with success in one, giving a success rate of 85%, and leaving 34 procedures for evaluation (adrenal CS, n = 2; ACS, n = 32). Of 14 patients with bilateral tumors, 10 had bilateral and 4 had unilateral overproduction. Of 20 patients with unilateral tumors, 11 had lateralization to the side of the tumor and the remaining had bilateral secretion. Cholesterol scintigraphy findings were concordant with those of AVS in 13 of 18 cases (72%) and discordant in 5 (28%). Conclusion: Laterality of ACS does not always correspond to findings on CT images. AVS is a safe and valuable tool for differentiation between unilateral and bilateral cortisol secretion and should be considered when operative treatment of ACS is a possibility.

Neoplasias das Glândulas Suprarrenais/diagnóstico , Glândulas Suprarrenais/metabolismo , Síndrome de Cushing/diagnóstico , Hidrocortisona/sangue , Hiperaldosteronismo/diagnóstico , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/complicações , Glândulas Suprarrenais/irrigação sanguínea , Glândulas Suprarrenais/diagnóstico por imagem , Adulto , Idoso , Cateterismo/métodos , Colesterol/administração & dosagem , Colesterol/química , Meios de Contraste/administração & dosagem , Síndrome de Cushing/sangue , Síndrome de Cushing/complicações , Diagnóstico Diferencial , Estudos de Viabilidade , Feminino , Veia Femoral/cirurgia , Humanos , Hidrocortisona/metabolismo , Hiperaldosteronismo/sangue , Hiperaldosteronismo/etiologia , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/química , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Cintilografia/métodos , Tomografia Computadorizada por Raios X
Front Horm Res ; 49: 104-113, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29894991


Pharmacological glucocorticoid treatment is associated with adverse metabolic consequences such as hypertension, overweight, reduced glucose tolerance, diabetes mellitus and ultimately increased mortality in cardiovascular disease. Here we review the evidence of detrimental effects of hormone replacement therapy in adrenal insufficiency (AI). Registry studies indicate increased cardiovascular mortality, hypertension, diabetes, and dyslipidemia in both primary and secondary AI, but when cohorts with carefully characterized patients are studied the picture is less clear, and recently patients with primary AI was reported to have less hypertension and lower body mass index than controls. Whether near physiological replacement therapy increase long-term cardiovascular morbidity and mortality in AI is still unclear.

Insuficiência Adrenal/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Diabetes Mellitus/etiologia , Dislipidemias/etiologia , Glucocorticoides/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversos , Hipertensão/etiologia , Doenças Cardiovasculares/induzido quimicamente , Diabetes Mellitus/induzido quimicamente , Dislipidemias/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente
J Clin Endocrinol Metab ; 103(4): 1696-1703, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29452421


Background: The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges. Objective: The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays. Methods: Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5% percentile. Results: Cortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes, respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and 60 minutes, respectively. Conclusions: LC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin stimulation that are lower than those based on immunoassays, possibly because cross-reactivity between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive tests for AI and false-negative tests for NCCAH.

17-alfa-Hidroxiprogesterona/sangue , Hiperplasia Suprarrenal Congênita/diagnóstico , Insuficiência Adrenal/diagnóstico , Cosintropina , Hidrocortisona/sangue , Adolescente , Hiperplasia Suprarrenal Congênita/sangue , Insuficiência Adrenal/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Espectrometria de Massas em Tandem , Adulto Jovem
Eur J Endocrinol ; 176(6): 705-713, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28298353


OBJECTIVES: The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum. DESIGN AND METHODS: Prospective study of DST was carried out in patients with suspected Cushing's syndrome (CS) (n = 49), incidentaloma (n = 152) and healthy controls (n = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST (n = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST. Of these, three had been misdiagnosed as having autonomous cortisol secretion. DST results were highly reproducible and confirmed in a replication cohort (n = 58). Patients with overt CS had significantly elevated post-DST sa-cortisol and sa-cortisone levels compared with controls; 23 of 25 with autonomous cortisol secretion had elevated sa-cortisone and 14 had elevated sa-cortisol. CONCLUSIONS: Simultaneous measurement of serum DXM and cortisol reduced false-positive DSTs by 20% and improved the specificity. S-DXM >3.3 nmol/L is sufficient for the suppression of cortisol <50 nmol/L. Measurement of glucocorticoids in saliva is a non-invasive and easy procedure and post-DST sa-cortisone was found particularly useful in the diagnosis of CS.

Adenoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico , Cortisona/metabolismo , Síndrome de Cushing/diagnóstico , Dexametasona/metabolismo , Hidrocortisona/metabolismo , Adenoma/metabolismo , Adolescente , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromatografia Líquida , Síndrome de Cushing/metabolismo , Feminino , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Saliva/química , Espectrometria de Massas em Tandem , Adulto Jovem