Download Bilateral Macronodular Adrenal Hyperplasia (BMAH)

Bilateral Macronodular Adrenal Hyperplasia (BMAH)
1. BMAH; primary adrenal over-secretion of cortisol, represents less than 1% of cases of endogenous CS1,2
2. First described in 19641
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. Epidemiology1,2
- 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 hypercortisolism2
- Rare published cases progressed to reach overt Cushing’s syndrome during a follow-up period of 7 years2
- 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
described1,2
- Hormone secretion from an increase in the number of adrenocortical cells rather than an augmented synthesis
per cell1
- Inefficient steroidogenesis;
o Precursors such as plasma 17-OH-progesterone, urinary 17-OH-corticosteroids(U17OHCS) can be
proportionally more elevated than UFC2
o Explain the incongruity of some subclinical cortisol hypersecretion despite massive adrenal
enlargement1
6. Imaging1,8,9
- 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 cm1,2
- Nodules are yellow due to their high lipid content, nodular diameter is more than 1cm and can reach 5cm and
more1,2
- Two different subtypes2
o Atrophic internodular cortex (type 1)
o Hyperplasia of both nodular and internodular tissue (type 2)
- Microscopic evaluation; composed of two cell types1,2
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 studies2,6
- 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 receptors1
- 77–87% of patients affected by BMAH had aberrant cortisol response to at least one stimulation1,2
- Vasopressin (V1) and serotonin (HT4) agonists induce the highest percentage of aberrant responses
Aberrant G-protein-coupled receptors
Clinical setting which stimulate the secretion of cortisol
Vasopressin
Serotonin
Catecholamine
GIP (Glucose-dependent insulinotropic polypeptide)
LH/hCG
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 hyperplasia3
- 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 cortisol-secreting 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
Paracrine production of
ACTH in bilateral
macronodular adrenal
hyperplasia
9.3 Other molecular mechanisms2
- MC2R or GNAS activating mutations
- PDE11A inactivating variants
- Rarely, PRKACA (a-catalytic subunit of protein kinase A) increased expression
10. Investigation
10.1 Test for Aberrant G-protein-coupled receptors1
- 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 cortisol-secreting 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. Best Pract Res Clin Endocrinol Metab
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): 111
5. Young Jr, WF et al. The Clinical Conundrum of Corticotropin-independent 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 ACTH-independent 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
Met
CA
PPNAD
AIMAH
2-7 cm
Contralaterel
atrophy
CT
Lipid rich,
enhanceing after
contrast
Unilat >6cm
Inhomogenous
Venous invasion
Surrounding
atrophic
intervening cortex
Normal size adrenal
gland, nodule
<5mm, may be 1-2
cm
Massive bilat
Lipid rich
adrenal
Low attenuate
enlargement,
nodularity, size 15cm
T1
low
T2
iso
low
low
low
hyperintense