Primary pigmented nodular adrenal disease (PPNAD), also known as micronodular adrenal
disease, is of unknown cause; it is a rare cause of Cushing's syndrome, the diffuse 2 to 3
mm micronodules may be dark or black in color. One-half occur as part of the Carney
Macronodular adrenal disease: a rare, non-ACTH-dependent form of Cushing's syndrome of
unknown cause. The adrenal glands may be huge.
Four times more common in females; peak in 3rd & 4th decades.
II. Manifestations of Steroid Excess
Altered fat distribution (glucocorticoid excess)
Central or "truncal" obesity (thin distal extremities & obese trunk)
"Moon" face, " buffalo
hump" of fat over upper thoracic spine, large
deposition of fat over chest and abdomen.
ACTH level suppressed if adrenocortical tumor present (level <20 pg/ml in the face of
suggestive signs and symptoms and elevated plasma cortisol levels is diagnostic).
Normal range is 3 to 31 mcg/dl but a diurnal variation exists (highest @ 7 a.m. and
lowest @ 11 p.m.) in normals.
Absolute levels may be high constantly
More often, 8 a.m. level high normal to high but usual decline does not occur by
A 4 p.m., plasma cortisol level over 30 mcg/dl is very suggestive
24-hour urine for 17 OH corticoids (the Porter-Silber chromogens) and creatinine -
May be falsely elevated in very obese patients, depressed patients, patients under great
stress, or alcoholics.
Allow 0.06 mg/lb of actual body weight for normal patient with obesity and report 17 OH
corticoid excretion as "mg per mg of creatinine excretion to correct for obesity.
(DHEA-sulfate and androstenedione) may be elevated in all forms of
Cushing's syndrome except iatrogenic form and that due to benign adrenocortical adenoma.
Rarely used since advent of urinary free cortisol measurement
Urinary 17-ketosteroids (17KS): Measures levels of metabolites of adrenal androgens
Of historical interest unless syndrome due to adrenocortical carcinoma, in which case,
17KS excretion may exceed 50 mg/day
Urinary "free" (unbound) cortisol: (best screening test for Cushing's)
To avoid false elevation, lab should do by high-pressure liquid chromatography
Values greater than four-fold normal are rare except in Cushing's syndrome
Suggested that 3 separate 24-hour urines be collected and average taken especially if
"pseudocushing's" from stress, depression, alcoholism, etc. may be present (may
need 3 normal free cortisol levels in urine to exclude diagnosis)
Measure 24-hour urinary 17OH corticoids for 2 days while giving dexa 500 microgms every
6 hours p.o. If 24-hour urinary 17 OHCS excretion exceeds 4 mg/day on 2nd day of urine
collection, Cushing's syndrome is suggested.
Too cumbersome to be used as routine screening test.
VI. How to Exclude ACTH-Independent Causes of Cushing's Syndrome
Begin with measurement of plasma ACTH (assay used must be able to detect to <20
If properly handled and measured, a value < 10 pg/ml is indicative of Cushing's
syndrome due to a non-ACTH-dependent cause.
Initial procedure: look at adrenal glands with
CT scan (good for nodules > 1 cm);
If mass present, may use MRI of adrenals for differential diagnosis
T2 - weighted signal progressively shorter for pheochromocytoma, carcinoma, adenoma,
and, finally, normal tissue
MRI of pituitary: microadenomas may be too small to see and up to 30% of
"normal" people have microadenoma (Nonsecretory?).
VII. How to Differentiate Between ACTH-Dependent Causes
Plasma ACTH: If value greater than 20 pg/ml, an ACTH-dependent form of Cushing's
Patients with ectopic ACTH production often (but not always) have values > 100
Patients with Cushing's "disease" (pituitary) may have ACTH levels in the
normal range (but inappropriately high for the level of plasma cortisol).
Since, of the ACTH-dependent forms, Cushing's "disease" (pituitary) is 4 times
as common, a test must have better than 80% sensitivity to perform better than chance
Each inferior petrosal sinus draining one side or the other of the pituitary
ACTH-secreting cells is catheterized. Obtain blood for ACTH simultaneously from each sinus
and from peripheral blood at 2 time points before and 3, 5, and 10 minutes after the
administration of ACTH-releasing hormone (corticotropin releasing hormone or CRH).
ACTH concentrations that are 2.5 times or more higher in central samples and that
increase after CRH suggest Cushing's "disease".
Six 24-hour urine collections required for 17OHCS and/or free cortisol.
As a result, hospitalization for accurate collections required; these are usually not
reimbursed by health insurers so rarely used now.
Collect two 24-hour urines for 17OHCS, free cortisol, and creatine, then start
dexamethasone 500 microgms every 6 hours po and on same day (3rd day) start 24-hour urine
for same parameters. Repeat this on day 4; on day 5, increase dexamethasone dose to 2 mg
every 6h and collect 24-hour urine for same parameters. Repeat this on day 6.
On low dose (total of 2 mg dexa/day), urinary 17OHCS suppressed to <
50% baseline value only in pseudocushings persons (not in Cushing's syndrome)
On high dose (total of 8 mg dexa /day), Cushing's "disease",
patient suppresses to < 50% of pre-dexa values but all other forms of Cushing's
syndrome either don't suppress at all or suppress to < 50% of pre-dexa values.
Sensitivity 75-85%; specificity 75-90%
For urinary free cortisol, suppression by > 90% on 2nd day of high dose dexa compared
to pre-dexa values suggestive of Cushing's "disease". (100% specificity; 86%
The overnight single 8 mg-dose dexamethasone suppression test (high dose test)
Give 8 mg dexa po at 11 p.m.; measure plasma cortisol 8 a.m. next day
Do if no suppression seen with 1 mg overnight dexa suppression
A decrease in plasma cortisol of 50% or more indicative of Cushing's "disease"
Sensitivity 89%; specificity 100%
The CRH stimulation test
CRH given I.V.
Interpretation: Cushing's "disease" patient shows increase in plasma ACTH
whereas patient with ectopic ACTH secretion shows no response.
Specificity 100%; sensitivity 93% using a post CRH increase in plasma ACTH level of
at least 34%
VIII. Ways to Localize ACTH-Secreting Tissue
Pituitary tumor secreting ACTH
MRI of pituitary with coronal views using gadolinium enhancement
Ectopic ACTH-secreting tumor
Octreotide scintigraphy (many tumors have somatostatin receptors and octreotide is a
IX. TREATMENT OF CUSHING'S SYNDROME
Agents modulating ACTH release (For Cushing's "disease") -- all tried; none
Pituitary tumor: 4500 rads in 25 fractional doses over 35 days with adjuvant use of
inhibitors of adrenal steroidogenesis initially (or perhaps chronically); may need heavy
charged particle radiosurgery. (sterotactic radiotherapy)