Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

Abstract

ACTH-Independent macronodular adrenal hyperplasia (AIMAH) is a rare cause of endogenous Cushing's syndrome (CS), in which clinical features usually become apparent only after several decades of life. This form of adrenal hyperplasia typically produces excess cortisol with overt or subclinical CS, but concurrent secretion of mineralocorticoids or sexual steroids can also occur. The diagnosis is suspected by bilateral adrenal nodules larger than 1 cm on incidental imaging studies or following the demonstration of ACTH-independent hormonal hypersecretion. The pathophysiology of this entity is heterogeneous and has been intensely explored in recent years. Several G-protein coupled receptors aberrantly expressed in the adrenal cortex have been implicated in the regulation of steroidogenesis and in the initial cell proliferation in AIMAH. Several familial cases of AIMAH have been recently described with the same pattern of aberrant hormone receptors in all affected members of the family. It is probable that additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition over time in the various nodules; other mechanisms, as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion have been rarely identified as the molecular mechanism in some cases. When systematically screened, most patients with AIMAH exhibit an in vivo aberrant cortisol response to one or various ligands suggesting the presence of aberrant adrenal receptors. The identification of these receptors creates the possibility of a specific pharmacological treatment isolated or associated with adrenalectomy. A hiperplasia adrenal macronodular independente de ACTH (AIMAH) é uma causa rara de síndrome de Cushing (SC) endógena, na qual alguns aspectos clínicos só se tornam evidentes depois de várias décadas de vida. Esta forma de hiperplasia adrenal caracteristicamente produz excesso de cortisol resultando na síndrome de Cushing franca ou subclínica, embora a secreção concomitante de mineralocorticóide, estrógeno e andrógenos também possa ocorrer. A suspeita diagnóstica é feita pela presença de nódulos adrenais bilaterais maiores que 1 cm, como achado incidental em exames de imagem ou pela demonstração de hipersecreção hormonal independente de ACTH. A fisiopatologia desta doença é heterogênea e tem sido intensamente estudada nos últimos anos. Vários receptores acoplados à proteína G, com expressão aberrante no córtex adrenal, têm sido implicados na regulação da esteroidogênese e no início da proliferação celular que ocorre na AIMAH. Diversos casos familiais de AIMAH foram recentemente descritos, e um mesmo padrão de expressão anormal dos receptores aberrantes foi observado em todos os membros afetados das famílias investigadas. Ao longo do tempo, é provável que ocorram, nos nódulos, eventos genéticos adicionais relacionados à regulação do ciclo celular, adesão e fatores de transcrição. Outros mecanismos moleculares, como mutações nos genes da proteína Gsα e do receptor de ACTH, ou ...

Results of unilateral adrenalectomy in subclinical Cushing's syndrome due to adrenocorticotropic hormone‐independent macronodular adrenal hyperplasia

“…AIMAH is characterized by benign, hyperplastic and macronodular adrenal glands, which are massively enlarged. It has been well established as a distinct, rare cause of Cushing's syndrome . Traditionally, the treatment for AIMAH has been bilateral adrenalectomy .…”

“…It has been well established as a distinct, rare cause of Cushing's syndrome. 1 Traditionally, the treatment for AIMAH has been bilateral adrenalectomy. 2,3 While the effectiveness and feasibility of the bilateral procedure has been well documented, patients are obliged to receive lifetime steroid replacement after the procedure, and subsequently, are susceptible to adrenal insufficiency crisis.…”

“…The most frequent presentation of adrenocorticotropic hormone (ACTH)-independent bilateral adrenocortical macronodular adrenocortical hyperplasia (AIMAH) is clinical or subclinical Cushing's syndrome (SCS). 1 Traditionally, bilateral adrenalectomy by either an overt or laparoscopic approach has been the most useful treatment for patients with AIMAH, although patients are obliged to receive lifetime steroid replacement after the procedure, and subsequently, are susceptible to adrenal insufficiency crisis. 2,3 In patients with SCS caused by AIMAH, adrenal nodules are generally found incidentally, and their autonomous cortisol secretion is not sufficiently abnormal to cause overt Cushing's syndrome (CS).…”

Cushing's syndrome of nonpituitary causes

“…Since the concept of aberrant hormone receptor stimulation leading to hypercortisolism was first postulated in 1971, at least 10 different aberrant receptors causing AIMAH have been identified [28,29]. Those identified are a diverse group of hormone receptors including gastric inhibitory polypeptide receptor, b-adrenergic receptors, vasopressin receptor, serotonin receptor, angiotensin II receptor, luteinizing hormone/human chorionic gonadotropin receptor, and leptin receptor [29]. Stimulation of these receptors leads to inappropriate downstream signaling with resultant growth of large monoclonal and polyclonal nodules in both adrenal glands [30,31].…”

“…Certain aberrant receptors causing hypercortisolism may be blocked with pharmacologic agents prior to surgery or as ongoing therapy [29]. This being said, bilateral adrenalectomy is most often recommended for patients with AIMAH; however, unilateral adrenalectomy has been advocated by some.…”