Cushings syndrome

Timea Bal M.D.

23. April 2013
3rd Dept of Internal Medicine

Definition
Cushing syndrome (CS) comprises the
symptoms and signs associated with prolonged
exposure to inappropriately elevated levels of
free plasma glucocorticoids

Harvey Williams Cushing (1869-1939)

He was the world's leading teacher of

neurosurgeons in the first decades of
the 20th century.
Under his influence neurosurgery
became a new and autonomous
surgical discipline.
He used x-rays to diagnose brain
tumors.
Used first electrocoagulation for
surgery
He first encountered the Cushing
reflex
He considerably improved the
survival of patients after difficult
brain operations for intracranial
tumors.
He used electrical stimuli for study of
the human sensory cortex.

Normal pattern of ACTH and cortisol

secretion

Pulsatile secretion
Circadian rythm

Frequency of causes of Cushings

syndrome
Diagnosis

Percent of patients

ACTH dependent Cushings syndrome

Cushings disease

68

Ectopic ACTH syndrome

12

Ectopic CRH syndrome

<<1

ACTH independent Cushings syndrome

Adrenal adenoma

10

Adrenal carcinoma

Micronodular hyperplasia

Macronodular hyperplasia

<<1

Mc Cune Albright syndrome

Pseudo Cushings syndrome
Major depressive disorder

Alkoholism

<<1

Common causes of ectopic ACTH

secretion
Small cell lung cancer 50%
Endocrine tumors of foregut origin 35%
Thymic carcinoid
Islet cell tumor
Medullary thyroid carcinoma
Bronchial carcinoid
Phaeocromocytoma 5%
Ovarian tumors 2%

Epidemiology
Iatrogenic Cushing's syndrome: iatrogenic Cushing's
syndrome must be more common than any other cause,
but is seldom reported
Ectopic ACTH syndrome:often not diagnosed, 1 % of
patients with SCLC have ectopic ACTH syndrome; SCLC
causes 50% of all cases of the syndrome
Cushing's disease: Pituitary ACTH-dependent Cushing's
syndrome is 5-6x more common than Cushing's syndrome
caused by benign and malignant adrenal tumors combined
Adrenal tumors: Adrenal masses are discovered
incidentally at autopsy or by radiographic studies in 1.3 to
8.7 % of adults
All other causes of Cushing's syndrome are extremely rare

Sex and age related incidence

Men had a 3x greater incidence of the ectopic ACTH syndrome, but
the increasing incidence of lung cancer in cigarette-smoking
women has narrowed that margin
Women are 3-8x more likely than men to develop Cushing's
disease, about 3x more likely to have either benign or malignant
adrenal tumors, and about 4-5x more likely to have Cushing's
syndrome associated with an adrenal tumor
Age-related incidence: increasing rapidly after age 50 years
Cushing's disease occurs mainly in women aged 25 to 45 years
In two small studies reporting on about 20 prepubertal children,
boys were affected more often than girls (18:2)
Adrenal tumors have a bimodal age distribution, with small peaks
in the first decade of life for both adenomas and carcinomas and
major peaks at about 50 years for adenomas and 40 years for
carcinomas

Symptoms and signs of Cushings

syndrome
The symptoms and signs of Cushing's syndrome
result directly from chronic exposure to excess
glucocorticoid
Establishing the diagnosis is often difficult
because none of the symptoms or signs are
pathognomic of the syndrome.
An important clinical clue to the presence of
glucocorticoid excess is the simultaneous
development and increasing severity of several
of these symptoms

Symptoms and signs of Cushings

syndrome

Centripetal obesity
Facial plethora
Glucose intolerance
Weakness, proximal myopathy
Hypertension
Psychological changes
Easy bruisability
Hirsutism
Oligomenorrhoea or
amenorrhoea
Impotence
Acne, oily skin
Abdominal striae
Ankle edema

Abdominal striae
Ankle edema
Backache, vertebral collapse,
fracture
Polyuria, polidipsia
Renal calculi
Hyperpigmentatione
Headache
Exophthalmos
Tinea versicolor infection
Abdominal pain

Skin lesions in Cushings syndrome

Skin atrophy: the stratum corneum is thinned, and there is
loss of subcutaneous fat, the skin eventually becomes
fragile due to these changes
Easy bruisability: Loss of subcutaneous connective tissue
due to the catabolic effects of glucocorticoid
Striae :Purple striae occur as the fragile skin stretches due
to the enlarging trunk, breasts, and abdomen, because the
increasingly thin skin does not hide the color of venous
blood in the underlying dermis
Fungal infections: tinea versicolor
Hyperpigmentation: Hyperpigmentation is induced by
increased ACTH.
ACTH is the principal pigmentary hormone in humans.
It acts via binding to melanocyte-stimulating hormone
receptors

Menstrual irregularities
80 percent of women had abnormal
menstrual cycles
correlates with increased serum cortisol and
decreased serum estradiol concentrations, but
not with serum androgen concentrations
may be due to suppression of secretion of
gonadotropin-releasing hormone by
hypercortisolemia

Signs of adrenal androgen excess

The major source of androgens in women are the adrenal
glands
In contrast, the major source of androgens in men is the
testes
men with Cushing's syndrome do not have signs of
androgen excess because cortisol has no androgenic
activity
adrenal carcinomas secrete large amounts of androgenic
precursors because they are inefficient at converting
cholesterol to cortisol
signs of androgen excess are usually mild in women with
ACTH-dependent Cushing's syndrome and do not occur in
women with adrenal adenomas
This signs: hirsutism, oily facial skin, acne, increased libido,
virilization (deepening voice, male body habitus etc. )

Skeletal abnormalities
Weakness and proximal muscle wasting, patients with more
severe disease may be unable to climb stairs or get up from
a deep chair
Hypokalemia, due to increased mineralocorticoid activity,
can accentuate the weakness in patients with severe
hypercortisolism
Bone loss osteoporosis:
vertebral compression fractures in 20 % of Cushing patients
Pathologic rib and long bone fractures
Osteonecrosis (aseptic necrosis) of the femoral heads
Low back pain is very common
Increased bone resorption can also lead to hypercalciuria
and renal calculi

Hypertension and cardiovascular risk

Cardiovascular disease, in particular moderate diastolic
hypertension, is a major cause of morbidity and death
in patients with Cushing's syndrome
Increased peripheral vascular sensitivity to adrenergic
agonists
Increased hepatic production of renin substrate
(angiotensinogen)
Activation of renal tubular type 1 (mineralocorticoid)
receptors by cortisol (this mechanism applies mainly to
patients with severe hypercortisolism, which is usually
due to ectopic ACTH secretion)
It is also possible that cortisol has a direct cardiotoxic
effect

Neuropsychological changes
Symptoms of psychiatric disease occur in over
one-half of patients with Cushing's syndrome of
any etiology
The most common psychologic symptoms:
Emotional lability
Agitated depression
Irritability
Anxiety
Panic attacks
Mild paranoia

Diagnosis of Cushings syndrome

None of the signs are pathognomic, and many are
nonspecific
The diagnosis must be confirmed by biochemical tests.
Exclude exogenous glucocorticoids (all glucocorticoids inhibit
ACTH secretion if given in sufficient doses)
Physiologic hypercortisolism
patients who are physically stressed, such as by a severe
bacterial infection;
patients with severe obesity, especially those with
visceral obesity or polycystic ovary syndrome
Patients with psychological stress, especially patients
with a severe major depressive disorder and
melancholic symptoms
Rarely, patients with chronic alcoholism
Pseudo Cushing syndrome

Diagnosis II.
80 % of patients with major depressive disorders
have increased cortisol secretion
However, cortisol hypersecretion, when present,
is usually minimal
even severely depressed patients with substantial
cortisol hypersecretion rarely develop clinical
Cushing's syndrome
abnormal cortisol secretion presumably results
from hypothalamic-pituitary-adrenal axis
hyperactivity

Adrenal incidentalomas and subclinical

Cushings
mild hypercortisolism without clinical manifestations of
Cushing's syndrome
Some adrenal incidentalomas secrete sufficient cortisol
to suppress ACTH, at least partially
The patients may have one or more of the effects of
endogenous cortisol over-secretion such as obesity,
hypertension, glucose intolerance or diabetes,
dyslipidemia, osteoporosis
Depending on the importance of cortisol secretion by
primary adrenal tumors, the spectrum of biochemical
abnormalities will vary

Diagnosis III.
2008 Endocrine Society Clinical Guidelines
At least two first-line tests should be abnormal to establish the
diagnosis of Cushing's syndrome
Late night salivary cortisol, urinary cortisol, and the low-dose
dexamethasone suppression tests are first-line tests
Urinary and salivary cortisol measurements should be obtained at
least twice
The urinary cortisol excretion should be unequivocally increased
(threefold above the upper limit of normal), or the diagnosis of
Cushing's syndrome is uncertain and other tests should be
performed.
The patient should undergo additional evaluation if the test results
are discordant or only slightly abnormal.
If test results are normal, the patient does not have Cushing's
syndrome unless it is extremely mild or cyclic.
No additional evaluation is necessary unless symptoms progress or
cyclic Cushing's syndrome is suspected.

Daily urinary cortisol excretion

Twenty-four hour urinary cortisol excretion provides a direct
and reliable practical index of cortisol secretion
ACTH and cortisol are secreted in discrete bursts, not only in
normal subjects but also in most patients with Cushing's
disease
Twenty-four hour urinary cortisol excretion is an integrated
measure of the serum free cortisol concentration
Its necessary to measure the urinary creatinine excretion
From the ages of 50 to 90, there is a progressive 50 percent
decline in creatinine excretion due primarily to a decline in
muscle mass
creatinine excretion is consistent from day to day, with no
more than 15 percent variability, allowing comparison of
samples

Low dose dexamethason suppression test

Exogenous dexamethasone substitutes for endogenous
cortisol in suppressing ACTH release
two forms: the 1mg overnight and the two-day 2 mg test
Screening tests for differentiating patients with possible
Cushings syndrome
High dose DXM test: used to distinguish patients with
Cushing's disease (Cushing's syndrome caused by pituitary
hypersecretion of corticotropin [ACTH]) from most patients
with the ectopic ACTH syndrome (Cushing's syndrome caused
by nonpituitary ACTH-secreting tumors)
The 2008 Endocrine Society Guidelines suggest a diagnostic
cortisol criterion of 1.8 mcg/dL (50 nmol/L)
It is possible that some patients with "normal" suppressibility
to dexamethasone are slow metabolizers of the agent so that
the effective dose is larger.

Salivary cortisol concentrations

Measurement of serum or salivary cortisol in the late
evening is based upon the fact that the normal evening
nadir in serum cortisol is preserved in obese and
depressed patients but not in those with Cushing's
syndrome
Saliva is easily collected and cortisol is stable in saliva
even at room temperature for several days
It is especially useful for patients suspected of having
cyclical or intermittent Cushing's syndrome
As with other cortisol assays, it is useful to evaluate at
least three samples from different days.

Late evening serum cortisol

concentrations
This test has usually been performed in the
hospital
The blood is taken after the patient appears to
be asleep
sleeping versus awake results have not been
evaluated systematically

CRH stimulation test

Etiology diagnose (especially for pituitary ACTH-dependent or
ectopic ACTH syndrome)
A newer approach is to combine a CRH stimulation test with a
dexamethasone suppression test(4mg ).
method :
1 g / kg of CRH is administered intravenously.
ACTH and cortisol levels are measured before CRH injection
and 15, 30, 45, 60, 90 and 120 minutes after injection.
A rise in the cortisol value of 20 percent or more above basal
level or a rise in the ACTH value of at least 50 percent above
basal level is considered evidence for an ACTH-dependent
lesion

False positives
Morbid obesity
Estrogen (pregnancy or OCP)
Phenytoin/Phenobarbital/Rifampin
(accelerated metabolism of dex)
Severe stress
Severe depression

Imaging diagnosis
Pituitary CT has a sensitivity of about 50% for
identifying microadenomas
MRI has increased sensitivity but is not 100%
predictive
If diagnostic doubt need bilateral inferior petrosal
sinus sampling for ACTH
Adrenal ultrasonography---first choice
Abdominal CT will allow identification of adrenal
pathology
Somatostatin scintigraphy to identify sites of
ectopic hormone production

Treatment of Cushings syndrome

Ideal therapy of Cushing's syndrome would
achieve the following goals :
Reverse the clinical manifestations by reducing
cortisol secretion to normal
Eradicate any tumor threatening the health of
the patient
Avoid permanent dependence upon
medications
Avoid permanent hormone deficiency

Treatment II.
Specific treatment may be delayed during
diagnostic testing or while drug adjustments
are made to achieve eucortisolism.
During this time, treatment of co-morbidities
such as hypertension, osteoporosis, and
diabetes should be instituted
The use of medications to prevent thrombosis
or bone loss should be considered.

Treatment of ectopic ACTH and CRH

syndromes
surgical excision
In patients with metastases limited to the liver,
resection or cryoablation of the metastases or even
liver transplantation may result in cure
Patients who were less than 50 years old, had primary
lung or bowel tumors, and had pretransplant
somatostatin treatment had the best prognosis
Nonresecable tumor: adrenal enzyme inhibitors
(ketokonazol, metyrapone, etomidate)
Bilateral surgical adrenalectomy may be used as an
alternative to mitotane

Primary adrenal diseases

Adrenal tumors should be removed with
unilateral adrenalectomy
Bilateral adrenalectomy is required for
bilateral micronodular and most patients with
macronodular adrenal hyperplasia
Bilateral adrenalectomy is now usually
performed by laparoscopy and causes
permanent adrenal insufficiency
Adrenocortical cancer: Mitotane

Course after effective therapy

Physical symptoms and signs of Cushing's syndrome
disappear gradually over a period of two to 12 month
Hypertension and glucose intolerance improve but
may not disappear
The osteoporosis of Cushing's syndrome begins to
improve about six months after the hypercortisolemia
is cured
In adults, psychiatric symptoms improve, but
underlying psychopathology may persist
In children, bone density and growth rate both increase
after treatment, although neither returns to normal

Pharmacologic use of glucocorticoids

Natural and synthetic glucocorticoids are used
in both endocrine and nonendocrine disorders
Endocrine: establish the diagnosis and cause
of Cushing's syndrome
for treatment of adrenal insufficiency and
congenital adrenal hyperplasia
Non-endocrine: glucocorticoids are used to
treat patients with inflammatory, allergic,
immunological disorders

Glucocorticoid structure
Chemical modification of
natural steroids in the 1950s
revealed a number of
structural features essential
for biological activity
The delta-4,3-keto-11beta,17-alpha,21trihydroxyl configuration is
required for glucocorticoid
activity and is present in all
natural and synthetic
glucocorticoids

Steroid structure
Most of the cortisol in serum is
bound to proteins, primarily
corticosteroid-binding globulin
(CBG) and albumin
In addition, much of the
biologically available cortisol
may be bound to erythrocytes
Because they have little or no
affinity for CBG, synthetic
steroids other than
prednisolone either bind
weakly to albumin (two-thirds)
or circulate as free steroid
(one-third)

Synthetic steroids
The half-lives of synthetic glucocorticoids are generally
longer than that of cortisol
Those subjects who metabolize glucocorticoids more
slowly may be more likely to develop side effects
Exogenous glucocorticoids are subject to the same
reduction, oxidation, hydroxylation, and conjugation
reactions as endogenous steroids
Certain drugs (eg, phenobarbital, phenytoin, rifampin,
mitotane) increase the metabolism of synthetic and
natural glucocorticoids similarly, particularly by
increasing hepatic 6-beta-hydroxylase activity of
CYP3A4

Comparison of representative
glucocorticoid preparations

Guidelines for pharmacological

glucocorticoid therapy
Initiate only if there is published evidence of objective
therapeutic benefit
Use only after other specific therapies fail
identify a specific therapeutic objective
Use objective criteria of response
Administer sufficient glucocorticoid for a sufficient time to
achieve the desired response
Administer glucocorticoid for no longer than is necessary to
achieve the desired response
Terminate if objective therapeutic benefit is not observed
when expected, if complications arise, or if maximum
benefit is achieved

Complications of chronic use

Potent synthetic glucocorticoids (eg, prednisone, methylprednisolone,
triamcinolone, dexamethasone, and betamethasone) have little
mineralocorticoid, androgenic, or estrogenic activity
As a result, the major systemic side effects are those of suppression of
hypothalamic-pituitary-adrenal function and Cushing's syndrome
HPA axis suppression: leads to adrenal atrophy and loss of cortisol secretory
capability
Not suppressed: Any patient who has received any non-parenteral dose of
glucocorticoid for less than three weeks
Patients treated with alternate-day glucocorticoid therapy at physiologic doses
Suppressed : Anyone who has received more than 20 mg of prednisone a day
for more than three weeks
Any patient who has clinical Cushing's syndrome
Uncertain suppression : Patients taking supraphysiologic doses of glucocorticoid
for three to six weeks may or may not have clinically important suppression of
hypothalamic-pituitary-adrenal function
cosyntropin stimulation test to evaluate the responsiveness of the adrenal if
therapy is going to be discontinued abruptly

Nelsons syndrome
a spectrum of symptoms and signs arising from an
adrenocorticotropin (ACTH)secreting pituitary
macroadenoma after a therapeutic bilateral adrenalectomy
clinical features observed relates to the local effects of the
tumor on surrounding structures, the secondary loss of
other pituitary hormones, and the effects of the high serum
concentrations of ACTH on the skin
The first case was reported by Nelson et al in 1958
Almost all cases of Nelson syndrome follow bilateral
adrenalectomy in patients who have Cushing disease due to
an ACTH-secreting pituitary adenoma
Very rare disorder
More common in woman

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