Cushing syndrome and bilateral adrenal enlargement
Macronodular adrenal hyperplasia can present dramatically with extreme glucocorticoid excess.
A 51-year-old obese woman with a complex medical and psychiatric history was admitted for evaluation of bilateral adrenal nodules. She had a history of depression, psychosis and osteoporosis. A recent fall resulted in a sacral fracture. Computed tomography scan confirmed this fracture and incidentally revealed large bilateral adrenal nodules. The patient reported problems with balance, swelling in her legs, nausea, recurrent rashes and easy bruising. Her psychiatric status made an outpatient evaluation impossible, and she was admitted for further assessment of her adrenal function.
Physical exam revealed a morbidly obese woman with a blood pressure of 136 mgHg/89 mmHg and a pulse of 89 beats per minute. Her face appeared Cushingoid with periorbital swelling and rubor. Her thyroid was palpable without nodularity. Her abdominal exam revealed visible superficial veins but no striae. She had large ecchymoses on her extremities and an erythematous, scaly, and papular rash in her inframam-mary creases and groin.
Random lab tests revealed a suppressed adrenocorticotropic hormone (ACTH) <5 pg/mL with an elevated serum cortisol. A low dose overnight dexamethasone suppression test revealed cortisol excess after administration of dexamethasone 1 mg at 11 p.m. with the next morning ACTH level <5 pg/mL, dexamethasone level 40 ng/dL and cortisol level 24.8 mcg/dL. These results suggested adrenal macronodular hyperplasia with Cushing syndrome. A cosyntropin stimulation test was performed to evaluate ACTH responsiveness to determine if she had ACTH-dependent or ACTH-independent macronodular hyperplasia. A vigorous sixfold increase in cortisol from 20.1 mg/dL to 125 mg/dL and 20-fold increase in 17-hydroxyprogesterone from 39 ng/dL to 931 ng/dL after IV cosyntropin (250 mcg) were consistent with ACTH-dependent macronodular adrenal hyperplasia. Her thyroid studies, insulin-like growth factor I level, and 24-hour urinary catecholamines and vanillylmandelic acid were all within normal limits.
A CT scan with an adrenal protocol was performed (see figure 1) that showed multiple low attenuation masses within both adrenal glands consistent with adrenal adenomas. The largest mass in the right adrenal gland was 5.2 cm × 3.8 cm × 3.2 cm and measured –3 Hounsfield units in attenuation. The largest mass in the left adrenal gland was 4.7 cm × 4.2 cm × 3.9 cm with attenuation between –12 and –1 Hounsfield units.
The patient was diagnosed with adrenal Cushing syndrome from ACTH-dependent bilateral adrenal macronodular hyperplasia. The patient had a bilateral adrenalectomy that revealed massive enlargement of both glands with multiple large cortical nodules consistent with macronodular adrenal hyperplasia. The left adrenal gland weighed 145.1 g and the right adrenal gland weighed 88.9 g. She was discharged from the hospital in her usual state of health on fludricortisone 0.1 mg daily and hydrocortisone 10 mg twice daily in addition to her regular medications.
Bilateral macronodular adrenal hyperplasia is a rare cause of Cushing syndrome, accounting for less than 1% of all adrenal Cushing syndrome. These patients usually present at an older age with long standing symptoms. The exquisite sensitivity of exogenous ACTH stimulation of cortisol and 17-hydroxyprogesterone production reflects the increased quantity of hormone producing cells in ACTH-dependent bilateral macronodular adrenal hyperplasia. ACTH-independent macronodular adrenal hyperplasia may have aberrant “illegitimate” or excess eutopic hormone receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, luteinizing hormone, human chorionic gonadotropin, follicle-stimulating hormone, serotonin and angiotensin that stimulate excess cortisol production. If aberrant adrenal receptors are present, clinically relevant screening tests should be performed, and a customized medical treatment plan can be designed to block the aberrant receptors and reduce excessive glucocorticoid production (see table).
As evident in this case, macronodular adrenal hyperplasia can present dramatically with extreme glucocorticoid excess. It is important to determine if the cortisol excess is an ACTH-dependent or ACTH-independent process. If ACTH-independent cortisol production is determined, the presence of aberrant adrenal receptors should be assessed as there are medical as well as definitive surgical therapeutic options for management of the Cushing syndrome.
Lisa Usdan, MD, is a Fellow in Endocrinology at Boston Medical Center.
Stephanie L. Lee, MD, PhD, is an Associate Professor of Medicine at Boston University School of Medicine and Director of Endocrine Clinics at Boston Medical Center.
For more information:
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- Christopoulos S, Bourdeau I, Lacroix A. Clinical and subclinical ACTH-independent macronodular adrenal hyperplasia and aberrant hormone receptors. Hormone Research. 2005;64:119-131.
- Doppman JL, Chrousos GP, Papanicolaou DA, et al. Adrenocortioctropin-independent macronodular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism. Radiology. 2000;216:797-802.
- Lieberman SA, Eccleshall TR, Feldman D. ACTH-independent massive bilateral adrenal disease (AIMBAD): a subtype of Cushing’s syndrome with major diagnostic and therapeutic implications. Eur J Endocrinol. 1994;13:67-73.