Human corticotropin releasing hormone test performance in the differential diagnosis between Cushing's disease and pseudo-Cushing state is enhanced by combined ACTH and cortisol analysis

Abstract

Objective: Corticotropin releasing hormone (CRH) test does not reliably distinguish Cushing's disease (CD) from normality or pseudo-Cushing state (PC). We assessed whether this could be achieved with a novel approach while preserving the ability of the test to distinguish CD from ectopic ACTH syndrome (EAS). Design: Retrospective/prospective study. Subjects and methods: We studied 51 subjects with CD, 7 with EAS, 26 with PC, and 31 controls (CT). Human CRH (hCRH) test was performed at 0830 h by measuring plasma ACTH and serum cortisol at K15, 0, 15, 30, 45, 60, 90, and 120 min. Results: The area under the curve-ACTH exhibited a significant negative correlation with baseline serum cortisol in CT and PC, but not in CD or EAS patients. ACTH response to hCRH was blunted in PC compared with CT, whereas peak serum cortisol was higher in PC than in CT subjects. These findings suggested that ACTH-dependent Cushing's syndrome can be diagnosed by the presence of two hCRH test parameters and excluded if either or both are absent. Application of i) basal serum cortisol O12 mg/dl and peak plasma ACTH O54 pg/ml, or ii) peak serum cortisol O21 mg/dl and peak plasma ACTH O45 pg/ml, had 91.3% (95% confidence intervals (CI) 81-97.1) and 94.8% (CI 85.6-98.9) sensitivity and 98.2% (CI 90.6-99.9) and 91.2% (CI 80.7-97) specificity respectively, in diagnosing ACTH-dependent Cushing's syndrome. The O14% serum cortisol increase from mean baseline values to the mean of 15 and 30 min values in patients who were positive for the test completely discriminated between CD and EAS. Conclusions: Simultaneous plasma ACTH and serum cortisol analysis enables the hCRH test to distinguish CD from PC and from normality, while preserving its ability to discriminate CD from EAS.

ACTH after 15 min distinguishes between Cushing's disease and ectopic Cushing's syndrome: a proposal for a short and simple CRH test

“…Because the pretest probability of CD is more than four times higher than that of ECS, a significant reduction in sensitivity can cause a greater proportional increase in false-negative results. In contrast to the results of the present analysis, several other reports have found serum cortisol to be a stronger predictor of CD than ACTH is (8,20,21). Those earlier analyses reported a cortisol increase of 20% or even less as the most suitable cutoff.…”

“…Mean ACTH increase at 15 and 30 min after CRH injection resulted in a maximal LR of 13.1 at a cutoff level of 77%, with 73% sensitivity and 94% specificity. When a previously hypothesized cutoff level of 9% was applied (8), specificity dropped to 50%. ROC curve analysis of the HDDS test showed the highest LR (8.9), with a cutoff value of R71% suppression of basal cortisol and a corresponding sensitivity of 64% and specificity of 93%.…”

Recommendations of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism for the diagnosis of Cushing’s disease in Brazil

“…Traditionally used for the differential diagnosis of ACTH-dependent Cushing's syndrome (85), the human CRH (hCRH) test was studied in 2009 to differentiate Cushing's syndrome from states of pseudo-Cushing's (86). Using statistical analysis to obtain maximum accuracy, the best criterion found has been a serum cortisol value higher than 12 µg/dL at baseline (absolute value, mean time -15 and 0 min) and peak ACTH higher than 54 pg/mL (absolute value) after a 100 µg IV infusion of hCRH, with a sensitivity of 91.3% and specificity of 98.2% for CD, which was better than both firstline methods and nocturnal serum cortisol.…”

“…Most commonly, a positive response is defined as an increase compared to baseline values (peak minus baseline) that is higher than 20% for cortisol and higher than 35% for ACTH with oCRH (135). For evaluations using hCRH, a positive response is considered for increases greater than 14% for cortisol and greater than 105% for ACTH (85,86).…”

Avaliação do eixo hipotálamo-hipófise adrenal no diagnóstico e na remissão da doença de Cushing

“…O diagnóstico etiológico de DC nos pacientes com SC é estabelecido por meio de: 1) ACTH sé-rico normal ou elevado; 2) supressão do cortisol sé-rico ou urinário após a administração de 8 mg de dexametasona "overnight" ou 2 mg 6/6h por 48h (Liddle II) (3,16); 3) presença de adenoma em imagem hipofisária por tomografia computadorizada (TC) [Sensibilidade (S): 20%-50%] ou por ressonância magnética (RM) (S: 60%-70%) (9,17). Devido à baixa sensibilidade da TC de sela túrcica, sugere-se sempre como método de imagem de escolha a utilização da RM de sela túrcica para a investigação da DC; 4) nos pacientes com imagem hipofisária negativa, é necessária a presença de gradiente do ACTH durante cateterismo bilateral simultâneo do seio petroso inferior com CRH ou com desmopressina (DDAVP) (3,18); 5) adicionalmente, pode ser utilizado o estímulo periférico do cortisol/ACTH ao CRH seguido ou não da supressão de dexametasona pelo Liddle II (1,19,20) ou do ACTH e/ou cortisol ao DDAVP como ferramenta auxiliar no diagnóstico da DC (Tabela 2).…”