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ACTH-independent macronodular adrenal hyperplasia

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Adrenocorticotropic hormone- (ACTH-)independent macronodular adrenal hyperplasia (AIMAH) is an infrequent cause of Cushing's syndrome (CS). AIMAH presents as incidental radiological finding or with subclinical or overt CS, occasionally with secretion of mineralocorticoids or sex steroids. The pathophysiology of this entity is heterogeneous. The aberrant adrenal expression and function of one or several G-protein-coupled receptors can lead to cell proliferation and abnormal regulation of steroidogenesis. In several familial cases of AIMAH, specific aberrant hormone receptors are functional in the adrenal of affected members. Additional somatic genetic events related to cell cycle regulation, adhesion and transcription factors occur in addition in the various nodules over time. Other mechanisms, such as Gsp or ACTH receptor mutations and paracrine adrenal hormonal secretion, have been rarely identified in other cases of AIMAH. The identification of aberrant receptors can offer a specific pharmacological approach to prevent progression and control abnormal steroidogenesis; alternatively, unilateral or bilateral adrenalectomy becomes the treatment of choice.

Section snippets

Initial descriptions of AIMAH

AIMAH was first described in 19643, and by 1994 only 24 similar cases had been published.4 Since then, more cases have been reported, and the characteristics of the disease have been increasingly delineated.5, 6, 7, 8 Various terms have been used, including massive macronodular adrenocortical disease, autonomous macronodular adrenal hyperplasia, ACTH-independent massive bilateral adrenal disease, giant or huge macronodular adrenal hyperplasia, and macronodular adrenal dysplasia.5, 6, 7, 8

AIMAH

Epidemiology

AIMAH presents a bimodal age distribution, with a rare subset presenting in the first years of life particularly with the McCune–Albright syndrome.9 Most AIMAH patients present in the fifth and sixth decades, a later age of onset compared with unilateral adenomas or Cushing's disease.1, 4, 5 This is also later than PPNAD, which occurs at a mean age of 18 years.5, 10 In contrast to the predominantly female distribution in most cases of CS, AIMAH is equally distributed between genders.2, 4, 5, 8

Genetic causes of AIMAH

In the majority of cases AIMAH appears to be sporadic. Several reports of familial clustering have been published with an autosomal dominant pattern of transmission.12, 13, 14, 15, 16, 17, 18 The prevalence of familial forms of AIMAH is not yet known, as systematic familial screening has not been conducted. In recently studied families with AIMAH, aberrant hormone receptors have been identified in their adrenal tissues (see later section), but the genes implicated have not yet been identified.15

Clinical and Laboratory Features

Patients with AIMAH are identified either following an incidental radiological finding or the investigation of an adrenal over-secretion syndrome.2, 4, 5, 6, 7, 8, 24, 25 The most common clinical presentation is subclinical, followed by clinical CS. At the time of diagnosis of the latter, subtle signs and symptoms consistent with CS have typically been present for a number of years. In one series, the diagnosis was delayed by a mean of 7.8 years.7 Plasma ACTH becomes progressively suppressed

Imaging in AIMAH

On CT scan, bilateral adrenal nodules of soft tissue density, measuring up to 5 cm, distort the normal adrenal glands (Fig. 1).6, 35, 36 In some cases the adrenal glands appear diffusely enlarged but lack distinct nodules. On MRI, T1-weighted images are hypointense relative to the liver and isointense relative to muscle. T2-weighted images tend to be hyperintense relative to the liver.35, 36 In contrast, the nodules of patients with chronic ACTH stimulation appear isointense relative to the

Pathology

The combined adrenal weight is usually >60 g and can reach 200 g per gland. The mean combined weight in one series was 132 g.35 In patients with Cushing's disease it was 22.9 g in a series of 30 patients.38 On cut sections, the nodules are yellow due to their high lipid content.11 The nodules are composed of two cell types: either with clear cytoplasm (lipid-rich) that form cordon nest-like structures, or with compact cytoplasm (lipid-poor) that form nest- or island-like structures.11, 33 The

Pathophysiology of AIMAH

Evidence for a primary adrenal alteration was provided by initial in vitro cell cultures from AIMAH tissues with a high rate of growth and cortisol production.40 Constitutive ACTH receptor (MC2R) mutation is not a common cause of adrenal hyperplasia or tumor formation.41, 42 In one patient with AIMAH, a C-terminal MC2R mutation (F278C) led to impaired desensitization and internalization and elevated basal cAMP.43 In a patient with hypersensitivity to ACTH, two mutations (C21R or S247G) were

Molecular mechanisms of aberrant hormone receptors

The development and function of the adrenal cortex requires tissue-specific expression of the appropriate hormone receptors and regulatory mechanisms for these receptors, involving cis-acting regulatory elements (promoters) and trans-acting factors (transcription factors, co-activators and co-repressors). The GIPR has been the most extensively characterized ectopic receptor in AIMAH. GIPR gene sequence analysis did not reveal mutations of coding or putative promoter regions in adrenals of

Investigation protocol for aberrant receptors

Investigative protocols have been developed to screen patients with adrenal CS to identify the regulation of steroid production by one or several aberrant receptors.95, 96 The strategy consists of modulating the plasma levels of diverse hormone (endogenous or exogenous) ligands for the potential aberrant receptors, while monitoring plasma levels of cortisol, other steroid hormones and ACTH. All tests are performed following an overnight fast and with the patient in a supine position for at

Treatment of AIMAH

Bilateral adrenalectomy by overt or laparoscopic approach has been the most useful treatment in patients with AIMAH and hormonal hypersecretion.4, 5, 7, 8 However, in patients with moderately increased hormonal production, unilateral adrenalectomy has been proposed as a safe and effective alternative; it is expected that, as the cell mass increases in the contralateral adrenal, a second adrenalectomy may be necessary.89, 97, 98 In patients with subclinical AIMAH, the decision for therapy should

Summary

In recent years, several new findings have contributed to a better understanding of the heterogeneity of pathogenesis in AIMAH. Aberrantly expressed G-protein-coupled receptors in the adrenal cortex appear to play a central role in the hormonal hypersecretion and cell proliferation in this disease. However, other molecular mechanisms – such as Gsp or ACTH receptor mutations, and adrenal paracrine hormonal secretion – can also be implicated in this disease. Together, these studies have

Acknowledgements

This work was supported by grant MT-13-189 from Canadian Institutes of Health Research.

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