Cushing syndrome
• Cushing's syndrome is a clinical features that
result from chronic exposure to excess
glucocorticoids of any etiology
• ACTH-dependent
1. pituitary corticotrope adenoma
2. ectopic secretion of ACTH by nonpituitary
tumor
• ACTH-independent
1. adrenocortical adenoma
2. adrenocortical carcinoma
3. nodular adrenal hyperplasia
4. iatrogenic (administration of exogenous
glucocorticoids )
• The term Cushing's disease refers specifically
to Cushing's syndrome caused by a pituitary
corticotrope adenoma.
Epidemiology
• Cushing's syndrome is generally considered a
rare disease.
• 1–2 per 100,000 population per year.
• Cushing's disease is caused by an ACTHproducing corticotrope adenoma of the
pituitary (75%)
• initially described by Harvey Cushing in 1912
• Cushing's disease more frequently affects
women
• prepubertal cases is more common in boys.
• ectopic ACTH syndrome is more frequently
identified in men.
• Only 10% of patients with Cushing's syndrome
have a primary, adrenal cause of their disease
and most of these patients are women.
• the medical use of glucocorticoids for
immunosuppression, or for the treatment of
inflammatory disorders, is the most common
cause of Cushing's syndrome.
Etiology
• Cushing's disease :at least 90% of patients is
caused by a corticotrope pituitary
microadenoma, often only a few millimeters
in diameter.
• Pituitary macroadenomas (i.e. tumors >1 cm
in size), are found in only 5–10% of patients
• usually occur sporadically
• very rarely can be found in the context of
multiple endocrine neoplasia type 1 (MEN1)
Ectopic ACTH production
• predominantly caused by occult carcinoid
tumors, most frequently in the lung, but also
in thymus or pancreas.
• Because of their small size, these tumors are
often difficult to locate.
• Advanced small cell lung cancer
• In rare cases medullary thyroid carcinoma or
pheochromocytoma
ACTH-independent
• The majority of patients with ACTHindependent cortisol excess harbor a cortisolproducing adrenal adenoma.
• Adrenocortical carcinomas may also cause
ACTH-independent disease and are often
large, with excess production of several
corticosteroid classes.
Clinical Manifestations
• excess glucocorticoid secretion overcomes the
ability of 11-HSD2 to rapidly inactivate cortisol
to cortisone in the kidney, thereby exerting
mineralocorticoid actions, manifest as :
1. diastolic hypertension
2. Hypokalemia
3. edema
• suppression of gonadotropins with
subsequent hypogonadism and amenorrhea
• suppression of the hypothalamic-pituitarythyroid axis, resulting in decreased TSH
(thyroid-stimulating hormone) secretion.
• more specific features are :
1. fragility of the skin
2. easy bruising
3. broad (>1 cm), purplish striae
4. signs of proximal myopathy, which becomes
most obvious when trying to stand up from a
chair without the use of hands or when
climbing stairs.
• The majority of clinical signs and symptoms
observed in Cushing's syndrome are relatively
nonspecific and include features such as:
1. Obesity
2. Diabetes
3. diastolic hypertension
4. Hirsutism
5. depression
• that are commonly found in patients who do not
have Cushing's
• Clinical manifestations of Cushing's do not
differ substantially among the different causes
of Cushing's.
• In ectopic ACTH syndrome, hyperpigmentation
of the knuckles, scars, or skin areas exposed to
increased friction can be observed and is
caused by stimulatory effects of excess ACTH
and other POMC cleavage products on
melanocyte pigment production.
• patients with ectopic ACTH syndrome, and
some with adrenocortical carcinoma as the
cause of Cushing's, may have
1. a more brisk onset
2. rapid progression of clinical signs and
symptoms
• Patients with Cushing's syndrome can be
acutely endangered by
1. deep vein thrombosis
2. pulmonary embolism due to a
hypercoagulable state associated with
Cushing's.
• psychiatric symptoms:
1. anxiety
2. depression
3. acute paranoid psychosis
4. acute depressive psychosis
• after cure, long-term health may be affected
by :
1. increased risk of cardiovascular disease
2. osteoporosis
3. vertebral fractures
Diagnosis
• 1- features with a potentially higher
discriminatory value
• 2 - excluding exogenous glucocorticoid use
1. increased 24-hour urinary free cortisol
excretion in three separate collections
2. failure to appropriately suppress morning
cortisol after overnight exposure to
dexamethasone
3. evidence of loss of diurnal cortisol secretion
with high levels at midnight, the time of the
physiologically lowest secretion
• midnight cortisol level greater than 200
nmol/L (>7.5 μg/dL) indicates Cushing’s
syndrome
• midnight Salivary Cortisol:a value greater than
2.0 ng/mL (5.5 nmol/L) has a 100% sensitivity
and a 96% specificity for diagnosis of
Cushing’s syndrome
Urinary Free Cortisol Excretion
• Normal values are less than 220 to 330
nmol/24 hours (80 to 120 μg/24 hours),
Patients should make two or three complete
consecutive collections
Low-Dose Overnight Dexamethasone
Suppression Tests
• In normal subjects, the administration of a
supraphysiologic dose of glucocorticoid results in
suppression of ACTH and cortisol secretion
• 1 mg of dexamethasone is given at midnight.
• A normal response is a plasma cortisol level of
less than 140 nmol/L (<5 μg/dL) between 8 and 9
a.m.
• a postdexamethasone cortisol value of less than
50 nmol/L (<2 μg/dL) effectively excludes
Cushing’s syndrome.
48-hour low-dose dexamethasone test
• plasma cortisol is measured at 9 a.m. on day 0
and again 48 hours later, after administration of
dexamethasone 0.5 mg every 6 hours for 48
hours
• Using a postdexamethasone plasma cortisol
concentration of less than 50 nmol/L (<2 μg/dL)
as the cutoff point
• this test is reported to have a 97% to 100% truepositive rate and a false-positive rate of less than
1%
Differential Diagnosis
• plasma ACTH levels are suppressed in cases of
autonomous adrenal cortisol excess, as a
consequence of enhanced negative feedback
to the hypothalamus and pituitary.
• patients with ACTH-dependent Cushing's have
normal or increased plasma ACTH,
• very high levels being found in some patients
with ectopic ACTH syndrome.
• In patients with confirmed ACTH-independent
excess, adrenal imaging is indicated
• preferably using an unenhanced CT scan. This
allows assessment of :
1. adrenal morphology
2. determination of tumor density in Hounsfield
Units (HU), which helps to distinguish
between benign and malignant adrenal
lesions
• For ACTH-dependent cortisol excess an MRI of
the pituitary is the investigation of choice
1. it may not show an abnormality in up to 40%
of cases because small tumors are below the
sensitivity of detection.
2. Characteristically, pituitary corticotrope
adenomas fail to enhance following
gadolinium administration on T1-weighted
MRI images
• In all cases of confirmed ACTH-dependent
Cushing's, further tests are required for the
differential diagnosis of pituitary Cushing's
disease and ectopic ACTH syndrome.
• most pituitary corticotrope adenomas still display
regulatory features, including residual ACTH
suppression by high-dose glucocorticoids and
CRH responsiveness.
• ectopic sources of ACTH are typically resistant to
dexamethasone suppression and unresponsive to
CRH
• if there is any other reason for doubt, the differential
diagnosis can be further clarified by performing
bilateral inferior petrosal sinus sampling (IPSS) with
concurrent blood sampling for ACTH in the right and
left inferior petrosal sinus and a peripheral vein.
• An increased central/peripheral plasma ACTH ratio >2
at baseline and >3 after CRH injection is indicative of
Cushing's disease, with very high sensitivity and
specificity.
• the results of the IPSS cannot be reliably used for
lateralization (i.e. prediction of the location of the
tumor within the pituitary),
• If the differential diagnostic testing indicates
ectopic ACTH syndrome, then further imaging
should include high-resolution, fine-cut CT
scanning of the chest and abdomen for lung,
thymus, and pancreas.
• If no lesions are identified, an MRI of the chest
can be considered as carcinoid tumors usually
show high signal intensity on T2-weighted
images.
• Furthermore, octreotide scintigraphy can be helpful
in some cases as ectopic ACTH-producing tumors
often express somatostatin receptors.
• Depending on the suspected cause, patients with
ectopic ACTH syndrome should also undergo
blood sampling for fasting
1. gut hormones
2. chromogranin A
3. Calcitonin
4. biochemical exclusion of pheochromocytoma
Treatment
• Overt Cushing's is associated with a poor
prognosis if left untreated
• In ACTH-independent disease, treatment
consists of surgical removal of the adrenal
tumor
Cushing's disease
• treatment of choice is selective removal of
the pituitary corticotrope tumor, usually via a
transsphenoidal approach.
• This results in an initial cure rate of 70–80%
• long-term follow-up is important as late
relapse occurs in a significant number of
patients.
• If pituitary disease recurs, there are several
options, including
1. second surgery
2. Radiotherapy
3. stereotactic radiosurgery
4. bilateral adrenalectomy
very severe Cushing
• difficult to control
1. hypokalemia
2. hypertension
3. acute psychosis
medical therapy
• it may be necessary to introduce medical
therapy to
1. rapidly control the cortisol excess during the
period leading up to surgery.
2. patients with metastasized, glucocorticoidproducing carcinomas
3. In case of ectopic ACTH syndrome, in which
the tumor cannot be located
bilateral adrenalectomy
• immediate cure
• requiring life-long corticosteroid replacement.
Oral agents
•
•
•
•
metyrapone
ketoconazole.
Mitotane,
etomidate can be used In severe cases of
cortisol excess, to lower cortisol. It is
administered by continuous IV infusion in low,
nonanesthetic doses.
• Metyrapone inhibits cortisol synthesis at the
level of 11-hydroxylase .
• Typical starting doses are 500 mg/tid
(maximum dose, 6 g)
• antimycotic drug ketoconazole inhibits the
early steps of steroidogenesis, 200 mg/tid
(maximum dose, 1200 mg).
• Mitotane, a derivative of the insecticide DDT, is
an adrenolytic agent that is also effective for
reducing cortisol.
• most commonly used in the context of
adrenocortical carcinoma, but low-dose
treatment (500–1000 mg per day) has also
been used in benign Cushing's.
After surgery
• After the successful removal of an ACTH- or
cortisol-producing tumor, the HPA axis will
remain suppressed.
• hydrocortisone replacement needs to be initiated
at the time of surgery and slowly tapered
following recovery, to allow physiologic
adaptation to normal cortisol levels.
• the HPA axis may require many months or even years
to resume normal function.