1. BMAH; primary adrenal over-secretion of cortisol, represents less than
1% of cases of endogenous CS 1,2
2. First described in 1964 1
3. Various terms 1
-
Massive macronodular adrenocortical disease
-
Autonomous macronodular adrenal hyperplasia
-
ACTH-independent macronodular adrenal hyperplasia
-
Giant or huge macronodular adrenal hyperplasia
-
Macronodular adrenal dysplasia
4. Epidemiology 1,2
-
Present in the fifth and sixth decades
-
Sporadic cases; higher female incidence in with a female-to-male ratio of 2–3 : 1
-
Familial cases; equal distribution between gender
5. Clinical and Laboratory Features
-
It more often presents as an incidental radiological finding with underlying subclinical hypercortisolism 2
-
Rare published cases progressed to reach overt Cushing’s syndrome during a follow-up period of 7 years 2
-
Urinary free cortisol (UFC) will rarely exceed the normal range, more attention should be paid to inadequate cortisol suppression after LDDST (1mg overnight) or the loss of diurnal rhythm of cortisol using late-night salivary cortisol
-
Concurrent secretion of cortisol and mineralocorticoids, estrone, or pure androgen production have been described 1,2
-
Hormone secretion from an increase in the number of adrenocortical cells rather than an augmented synthesis per cell 1
-
Inefficient steroidogenesis;

o Precursors such as plasma 17-OH-progesterone, urinary 17-
OH-corticosteroids(U17OHCS) can be proportionally more elevated than UFC 2 o Explain the incongruity of some subclinical cortisol hypersecretion despite massive adrenal enlargement 1
6. Imaging 1,8,9
-
Bilateral adrenal nodules of soft tissue density, measuring up to 5 cm, distort the normal adrenal glands
-
MRI; T1-weighted images are hypointense, T2-weighted images tend to be hyperintense
-
CT; lipid rich, homogenous, intence enhancement, no blood/calcification/necrosis
-
Occasionally there is an asymmetric development of nodules, leading to the erroneous diagnosis of unilateral pathology
7. Pathology
-
Adrenal weight is usually >60 g and can reach 200 g per gland, size may reach 10-20 cm 1,2
-
Nodules are yellow due to their high lipid content, nodular diameter is more than 1cm and can reach 5cm and more 1,2
-
Two different subtypes 2

o Atrophic internodular cortex (type 1) o Hyperplasia of both nodular and internodular tissue (type 2)
-
Microscopic evaluation; composed of two cell types 1,2 o Clear cytoplasm (lipid-rich) that form cordon nest-like structures o Compact cytoplasm (lipid-poor) that form nest- or island-like structures
8. Genetic studies 2,6
-
Heterogeneous genetic cause underlies BMAH (Table2) o Somatic gene mutation occurring during the early phases of embryogenesis or o Inherited germline mutation
-
The most recent finding is the discovery germline mutation of
ARMC5 in approximately 50% of patients with apparently sporadic
BMAH and in large families with BMAH
-
Armadillo repeat containing 5(ARMC5) o Located on Chromosome 16p11.2 o Unknown function; behaved as a tumor suppressor gene, second hit is needed for disease development o Its inactivation decreased the expression of MC2R and steroidogenic enzymes o In internodular hyperplasia, only germline mutation was present but several somatic genetic events occurred in the different macronodules o Thus, second somatic ARMC5 or other second hits may contribute to progression of macronodules

9. Pathophysiology; adrenal process of growth and hypersecretion appears to be explained through different mechanisms
9.1
Aberrant G-protein-coupled receptors;
-
The aberrant stimulation of steroidogenesis can be driven by the expression of ectopic receptors 1
-
77–87% of patients affected by BMAH had aberrant cortisol response to at least one stimulation 1,2
-
Vasopressin (V1) and serotonin (HT4) agonists induce the highest percentage of aberrant responses
Aberrant G-protein-coupled receptors
Vasopressin
Serotonin
Catecholamine
GIP (Glucose-dependent insulinotropic polypeptide)
LH/hCG
Clinical setting which stimulate the secretion of cortisol
Physiological stimuli of vasopressin secretion (such as upright posture)
Cisapride and Metoclopramide used
Upright posture, insulin-induced hypoglycemia or exercise
Following meals (low fasting plasma cortisol levels)
Pregnancy, Postmenopause

9.2
Paracrine production of ACTH in bilateral macronodular adrenal hyperplasia 3
-
A study reveals that the cortisol production is controlled both by aberrant membrane receptors and by corticotropin that is produced within the adrenocortical tissue, act as a local amplifier of action of receptors
- mRNA encoding the ACTH precursor proopiomelanocortin was detected in all 26 hyperplastic adrenal samples
-
Moderate/intense immunostaining for ACTH was detectable in
BMAH samples but not present in normal cortex or cortisolsecreting adenomas
-
ACTH secretion was not regulated by CRH, dexamethasone or the glucocorticoid receptor antagonist mifepristone
-
Co-expression in the ACTH-positive cells of insulin-like 3, a
Leydig and luteal-cell marker suggests an abnormal tissue differentiation occurring event during embryogenesis in common gonadal–adrenal progenitor
-
ACTH secretion was confirmed by ACTH gradient in adrenal vein sampling
9.3 Other molecular mechanisms
-
2
MC2R or GNAS activating mutations
-
PDE11A inactivating variants
Paracrine production of
ACTH in bilateral macronodular adrenal hyperplasia

-
Rarely, PRKACA (a-catalytic subunit of protein kinase A) increased expression
10. Investigation
10.1
Test for Aberrant G-protein-coupled receptors 1
-
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
-
Response; % increase steroid levels from the baseline in the absence of an increase in ACTH level o Partial response ; 25–49% o Positive response; >50%
10.2
Adrenal venous sampling (AVS) 5
-
Adrenal venous sampling was completed after an overnight fast between 7 and 10 a.m. on the second day of either low dose or high-dose dexamethasone administration
-
Concentrations of cortisol and epinephrine were measured in blood obtained from both adrenal veins[AV] and the external iliac vein (for determination of peripheral venous [PV])
-
Successful catheterization; AV:PV epinephrine gradients
(AV>PV 100 pg/ml.)

-
Cortisol AV:PV gradient > 6.5 was consistent with a cortisolsecreting adenoma
-
Cortisol lateralization ratio
≥
2.3 was consistent with autonomous cortisol secretion from predominantly 1 adrenal gland
11. Treatment
-
Surgery; o Bilateral adrenalectomy; the most useful treatment in patients with AIMAH and hormonal hypersecretion o Unilateral adrenalectomy
-
Patient with moderately increased hormonal production
-
UFC more than two times the upper limit of normal and marked asymmetry of adrenal enlargement
-
Adrenal venous sampling to select which adrenal to remove but standardization for data interpretation is lacking
-
Subclinical BMAH; o Consider therapy in case with cortisol excess, such as HT, diabetes, osteoporosis, apparent brain atrophy or neuropsychological manifestations o Evaluate annually for progression, clinical cortisol excess
-
Medication; BMAH with aberrant GPCR can benefit from specific medical therapy

References
1.
Lacroix A. ACTH-independent macronodular adrenal hyperplasia.
2009;23:245-59.
2.
Agostino De Venanzi, et al. Primary bilateral macronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes 2014;
21: 177-184.
3.
Louiset E, Duparc C, Young J, et al. Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. N Engl J Med 2013;
369:2115–2125.
4.
Mermejo LM, et al. ACTH-Independent Macronodular Adrenal
Hyperplasia. Endocrinol Metab; 2011:26(1): 1-11
5.
Young Jr, WF et al. The Clinical Conundrum of Corticotropinindependent Autonomous Cortisol Secretion in Patients with
Bilateral Adrenal Masses.World J Surg (2008) 32:856–862.
6.
Assie´ G, Libe´ R, Espiard S, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N
Engl J Med 2013; 369:2105–2114.

7.
Martins RG, Agrawal R, Berney DM, et al. Differential diagnosis of adrenocorticotropic hormone-independent Cushing syndrome: role of adrenal venous sampling. Endocr Pract 2012; 18:e153–e157.
8.
Rockall et al. CT and MRI Imaging of the Adrenal Glands in ACTHindependent Cushing Syndrome. Radiographics. 2004 Mar-
Apr;24(2):435-52.
9.
Sahdev et al. Imaging in Cushing's Syndrome. Arq Bras Endocrinol
Metab 2007;51/8.

Lesion
Adenoma 2-7 cm
Contralaterel atrophy
Met
CA Unilat >6cm
Venous invasion
PPNAD Surrounding atrophic intervening cortex
CT
Lipid rich, enhanceing after contrast
Inhomogenous
T1 low low
T2 iso low

AIMAH
Normal size adrenal gland, nodule
<5mm, may be 1-2 cm
Massive bilat Lipid rich adrenal enlargement,
Low attenuate nodularity, size 1-5cm low hyperintense