cushings-complete-keil-findling.ppt

to the
WELCOME
Cushing’s Support
and
Research Foundation
Courtesy of www.CSRF.com

What is Cushing’s?
Cushing’s Support & Research Foundation
Cushing’s Syndrome is a relatively rare endocrine system disorder
caused by the body’s exposure to excessive amounts of the hormone
cortisol.
Cushing’s Syndrome has many symptoms, including weight gain and a
change in appearance and may go undiagnosed for many years.
Recent studies show that 3-5% of poorly controlled diabetics may
have Cushing’s.
The most common cause of Cushing’s is the prolonged use of
cortisone containing drugs, such as prednisone, which are commonly
used to treat severe asthma or arthritis.
Approximately 10-15 people per million per year are affected with
Cushing’s due to the over-production of cortisol by the body’s adrenal
glands.
Cushing’s can be fatal if not correctly diagnosed and treated.
Cushing’s was first reported by the American neurosurgeon, Dr.
Harvey Cushing in 1932.

What is Cushing’s?
Normally, the pituitary gland, located at the base of the brain,
releases ACTH (adrenocortiocotopin hormone) that stimulates the
adrenal gland (located above the kidney) to release the exact amount
of cortisol needed by the body.
There are several situations that can cause over-production of cortisol
by the body’s adrenal glands:
1. A pituitary tumor can secrete excess ACTH. The excess ACTH
causes over-production of cortisol by the adrenal glands.
Cushing’s due to a pituitary tumor is called Cushing’s Disease
and all other causes are termed Cushing’s Syndrome.
2. A benign or malignant tumor on the lung or other organ can also
secrete excessive amounts of ACTH, which again, stimulates
over-production of cortisol by the adrenal glands.
3. Tumors of the adrenal gland can secrete too much cortisol by
themselves.
With Cushings
Normal Appearance

What are the Symptoms?
Cortisol affects almost every bodily function, thus the symptoms are
multiple and often non-specific.
Cushing’s cannot be diagnosed based on symptoms alone and
symptoms vary widely from one patient to another.
Not all patients experience every symptom and symptoms do not
seem to appear in any particular order.
Some patients report rapid changes, while others experience a slow
onset.
Cushing’s has many symptoms, but if the disorder progresses, most
patients will report:
weight gain
a redistribution of fat to the face (moon face), the upper back
(buffalo hump) and in the neck above the clavicle
thinning extremities due to muscle weakness
Some physicians consider purple striae (stretch marks) more specific
to Cushing’s.

What are the Symptoms?
Cortisol affects almost every bodily function, thus the symptoms are
multiple and often non-specific.
Cushing’s cannot be diagnosed based on symptoms alone and
symptoms vary widely from one patient to another.
Not all patients experience every symptom and symptoms do not
seem to appear in any particular order.
Some patients report rapid changes, while others experience a slow
onset.
Cushing’s has many symptoms, but if the disorder progresses, most
patients will report:
• weight gain
• a redistribution of fat to the face (moon face), the upper back
(buffalo hump) and in the neck above the clavicle
• thinning extremities due to muscle weakness
Some physicians consider purple striae (stretch marks) more specific
to Cushing’s.

Abdominal weight gain
Red, round ‘moon’ face
Thinning extremities
‘Buffalo hump’
High blood pressure
High blood sugar
Muscle weakness
Osteoporosis/Fractures
Infections
Blood clots
Visual field defects
Easy bruising
Thinning skin
Poor wound healing
Acne
Purple striae
Hirsutism
Female balding
Menstrual irregularity
Sleep disorders
Excessive hunger
Excessive thirst
Frequent urination
Sweating
Anxiety
Confusion
Concentration loss
Memory loss
Depression
Suicidal thoughts
Panic attacks
Illustration from Mayo Clinic Family Health Book, 2d. ed, 1996
Symptoms Vary
And may include
any number of these:

Pituitary Adenomas
Pituitary Adenomas are small, usually non-cancerous, tumors which cause
hormonal imbalances. There are two types of Pituitary tumors.
Non-secretory tumors can cause problems because of their large size, or
they prevent normal hormone production.
Secretory tumors produce too much of a particular type of hormone. There
are several disorders caused by secretory tumors depending on the type of
hormone the tumor secretes.
Pituitary Adenomas causing Cushing’s account for approximately 80% of
all Cushing’s cases. They are 5x more frequent in women.
Most adenomas causing Cushing’s are small, less than 10mm.
Pituitary adenomas can cause headaches.
Large pituitary adenomas can affect the optic nerve and invade adjacent
structures such as the cavernous sinus.
Origins of Cushing’s

Adrenal tumors release excessive amounts of cortisol
independently of ACTH production by the pituitary
Most adrenal tumors are non-cancerous adrenal adenomas and
are located only on one adrenal gland.
Carcinomas (cancerous tumors) may also cause high hormone
levels and rapid development of Cushing’s symptoms.
Over all, adrenal tumors are rare, causing about 15% of all cases
of Cushing’s syndrome.
Adrenal Tumors
With Cushings Normal Appearance

Another very rare cause of Cushing’s is termed macronodular
adrenal hyperplasia.
The adrenal glands are enlarged and appear to have multiple
nodules, which may be pigmented or non-pigmented.
Macronodular hyperplasia usually affects both adrenal glands
rather than just one.
Some macronodular hyperplasias respond to hormones such as
gastric peptides, adrenalin, and vasopressin. An increase in that
hormone can cause a rise in cortisol.
Patients affected with macronodular adrenal hyperplasia should
be studied extensively to determine responses to hormones other
than ACTH. Some conditions can be treated by medications.
It is becoming apparent that some bilateral macronodular
hyperplasias can be inherited.
Adrenal Macronodular Hyperplasia

Is caused by other ACTH-secreting tumors in the body.
Small tumors of the lung, tumors of the thymus gland,
tumors of the pancreas and carcinoma of the thyroid
can secrete ACTH.
These types of tumors can cause a slight differentiation
in symptoms – higher blood pressure, lower potassium
and possible weight loss due to underlying cancer.
Ectopic Cushing’s Syndrome

Steroid Usage - Exogenous
Exogenous Cushing’s is caused by a patient’s use of corticoid
steroids in the treatment of other diagnosed conditions like
severe asthma, rheumatoid arthritis or serious skin conditions.
Also called Iatrogenic Cushing’s syndrome, some sources
consider this the most likely cause of Cushing’s syndrome. The
number of patients being treated with immunosuppressive
medication out numbers the cases caused by tumors.
This type of Cushing’s may
be relieved by dosage adjustments
or a change to another type of
medication.
Patients must not stop medications
without consulting a medical
professional.

Diagnosis
Is it Cushing’s?
Many Cushing’s patients have long histories
of misdiagnoses since symptoms vary, are
common in the general population, may be
subtle and often develop slowly.
Many of the tests used to diagnose Cushing’s
depend on the body’s “feedback” system that
maintains cortisol levels in a normal range.
The hypothalamus secretes a hormone called
CRH that stimulates the pituitary to release
ACTH. ACTH then stimulates the adrenals to
make more cortisol.
As cortisol levels rise, a “negative feedback”
mechanism lets the hypothalamus and
pituitary gland know that there is enough
cortisol, thus as cortisol levels rise, they
normally decrease their production of CRH or
ACTH. This does not occur in a patient with
Cushing’s.
The Hypothalamic-Pituitary-Adrenal Axis
From Endocrinology, Hadley, M.C. 1988, Prentiss
Hall, N.J.

Diagnosis of Cushing’s
The first step in diagnosing Cushing’s is to determine whether
the patient has high levels of cortisol.
Cortisol levels vary throughout the day, making testing more
difficult. The normal “diurnal rhythm” for cortisol secretion is
that cortisol and ACTH levels are the highest in the morning
and the lowest at 11PM to midnight.
Mild or cyclical cases of Cushing’s can be very difficult to
diagnose and repeated testing is very often required.
Cyclic Cushing’s will only show abnormal test results when the
tumor is active.
The second step in the diagnosis of Cushing’s is to determine
whether the cortisol production is dependent on ACTH
(pituitary or ectopic sources) or ACTH independent (adrenal
tumors). This is termed the “differential diagnosis”.

Screening Tests for Cushing’s

Late Night Salivary
24-hour Urinary Free Cortisol
This is the latest diagnostic test for Cushing’s. Elevated cortisol
levels between 11PM and midnight are the earliest indications of
the disease. This is an easy test for patients to perform and
provides 93-100% accuracy for the diagnosis of Cushing’s.
Normal levels of cortisol at this time of day virtually eliminates a
diagnosis of Cushing’s.
This test is considered the gold standard diagnostic test.
However, additional testing is always needed. There are
conditions not related to Cushing’s that provide the
same results. Many Cushing’s patients will have a normal
24 hour urine free result from time to time, thus a normal
result does not exclude the diagnosis of Cushing’s.
With Cushings
Normal Appearance
In patients with equivocal results, combination of
dexamethasone suppression with a stimulation test using the
hypothalmic hormone CRH can be useful in making the
diagnosis of Cushing’s syndrome. This study should only be
performed in a setting by endocrinologists who have had
experience with the test to ensure it is performed properly.
Dex-CRH Stimulation

Dexamethasone Suppression
This test has been used for 40 years. It is still widely used and
useful when combined with other tests. Patients take 1 mg of
dexamethasone, a synthetic steroid, at 11 pm and cortisol and
ACTH are measured at 8 the next day. Normal persons will show
low ACTH and low cortisol due to proper functioning of the
feedback system. Cushing’s patients “do not suppress” thus the
cortisol levels remain elevated. When performed accurately this
test provides a 95-97% efficiency in the diagnosis of Cushing’s.
Petrosal Sinus Sampling
This test is useful in differentiating pituitary and ectopic sources of
ACTH. PSS uses catheters inserted through the large veins in the
groin to sample ACTH levels as they drain from the pituitary veins.
This test is most useful when combined with CRH stimulation and
can in some cases localize the pituitary tumor to one side of the
pituitary gland.
This particular study needs to be performed by a skilled
interventional radiologist with extensive experience. It has a
diagnostic accuracy rate is between 95-98%.

Direct Visual – MRI & CT Scan
If ACTH levels are increased, the next step in the diagnosis is to
determine the location of the ACTH producing tumor. Hopefully
direct visual imaging associated with MRI of the pituitary gland will
show the tumor. If a tumor greater than 5mm is clearly identified,
further testing may not be needed, however care needs to be
exercised as approximately 10% of the population have small non-
functioning pituitary tumors. In about 50% of cases, the pituitary
tumor is so small that it can not be seen with conventional
imaging techniques.
If ACTH is elevated, and the pituitary MRI is “normal”, further
testing is required to differentiate between unseen pituitary
sources and an ectopic tumor located elsewhere in the body.
If ACTH levels are low or not detectable, a CT or MRI of the adrenal
glands almost always identifies the tumor or tumors.
With Cushings
Normal Appearance

Differential Diagnosis
Once it is established that cortisol levels are elevated, several tests
are used to determine the cause of Cushing’s:
Measurement of serum ACTH – ACTH will be elevated in patients
with pituitary tumors and ectopic tumors. ACTH will be low or not
detectable in patients with adrenal tumors.
High Dose Dexamethasone Suppression Test
Endocrinologists may perform high-dose dexamethasone
suppression testing to help distinguish a pituitary from
a non-pituitary ACTH-secreting tumor.
Whole Body Imaging
If the source of ACTH secretion is thought to be ectopic, often
whole body images are performed.
Some larger tumors may be identified using CT or MRI scans
PET scans can also be useful in identifying ectopic tumors
Ectopic tumors are successfully located in the majority of cases,
however small tumors can remain unseen or “occult”.

Cushing’s in Children
Most of the symptoms of Cushing’s in children are
similar to that of adults. An added concern
however, is the symptom of growth failure or a
deceleration of growth accompanied by weight
gain.
It is vital that children be evaluated by Pediatric
Endocrinologists who are experienced with
adjusting test requirements for their size.
The best diagnostic for children is the Urinary Free
Cortisol test.
The most common cause of Cushing’s in infants
and toddlers is an adrenal tumor.
The most common cause of endogenous Cushing’s
in older children is an ACTH secreting pituitary
tumor.
With Cushings
With Cushings
Normal Appearance
Normal Appearance

Treating Cushing’s
The first choice in treating pituitary tumors is surgical removal.
Transsphenoidal surgery is done through the nose and is performed by
a neurosurgeon. It is important to find a surgeon who specializes in
pituitary surgery. Long-term follow up is required after tumor
removal. Hormone supplementation post-surgery needs to be
monitored by an experienced endocrinologist. Provided that normal
pituitary tissue remains, normal pituitary function returns gradually.
If the tumor or part of it can not be removed surgically, radiation and
medical treatments may be required. In some cases a small amount of
tumor cells remain. These may grow and cause a recurrence.
Radiating the pituitary gland may take as long as 3 years to be
effective. In the mean time, medical treatments are needed to control
the cortisol production and it’s complications such as high blood
pressure, high blood sugar, osteoporosis, etc.
Pituitary Adenomas

Small non-cancerous adrenal tumors (adenomas) can be removed
with the less invasive laparoscopic surgery techniques. Larger
cancerous tumors are removed using open surgical techniques.
If a rare cancerous tumor is found, surgery may be followed by
radiation or chemotherapy.
In cases of bilateral adrenal hyperplasia, both glands may need to
be removed. In this case, the patient will need hormone
replacement for the rest of their life.
Adrenal Tumors
With Cushings
Normal Appearance

Recovery
Patients and their family should not expect immediate recovery following
surgery.
Just as each patient’s symptoms are unique, so is the recovery period.
Some patients move steadily through the process. Others experience a
process of small steps of improvement with multiple set backs along the
way.
The length of time the patient’s body was exposed to the excessive
cortisol is an indication for the length of the recovery period.
Patients who have had pituitary surgery or radiation should be
periodically evaluated for deficiencies of other hormones such as thyroid
and Growth Hormone.
During the recovery process, it is not unusual to experience
fatigue, muscle aches and pains, a lack of appetite and mild
nausea.

Recovery
Patients must be informed about adrenal insufficiency “sick day rules”.
Patients who are prescribed physiological replacement doses of cortef
need to know that additional doses of cortef are required during acute
illnesses to prevent serious problems such as low blood sugar level or a
drop in blood pressure.
Following curative surgery, cortisol levels drop to virtually zero. Cortisol
is needed by the body, thus replacement medication is needed.
For patients with pituitary or single adrenal tumors, the dose is gradually
tapered down to physiological replacement levels, so that the patient’s
own HPA axis recovers. This can take a substantial period of time. Most
patients are able to stop replacement medication after 1 year.
After physiological replacement levels are reached, most patients are
tapered to lower levels using the short acting drug, hydrocortisone
(Cortef).
Follow up 24 hour urine for cortisol or MRI / CT scans may be
necessary to evaluate recurrences of tumors.

Recovery
It is not uncommon for patients who are affected by a life threatening
disease to experience depression. Some studies indicate that
Cushing’s may have the highest occurrence at 90%. This is partly due
to the effects of excessive cortisol on the brain.
Continued evaluation of symptoms by your
health care professionals is also necessary to
help identify and treat the symptoms.
Medications to treat the symptoms may need
to be re-evaluated throughout the recovery
process.
A positive attitude is the best recourse.
Continually focusing on the progress you have
made is the only way to see through both the
good and bad times.
In the End
With Cushings
Normal Appearance

• Provide information and support for Cushing’s
Syndrome/Disease patients and their families.
• Increase awareness and educate the public.
• Be a resource of information and support for health care
professionals.
• Raise and distribute funds for Cushing’s research.
Mission
Organization
• The CSRF was incorporated in 1995 in the state of
Massachusetts as a non-profit organization.
• We are an Associate Member of the National
Organization for Rare Disorders(NORD) and The
Endocrine Society
• Our Medical Advisory Board consists of world renowned
Endocrinologists and Surgeons who specialize in
Cushing’s Disorders.
• The CSRF is primarily funded by its membership and
donations.

And ‘NORDLYS’
www.northern-lights.no
For the use of the
Aurora Borealis photos
Copyright © 2003 Nordlyssenteret
www.CSRF.net
It’s a long
but worthwhile
journey!
Reviewed by:
James Findling, MD, Endocrinology at
St. Luke’s Medical Center in Milwaukee, WI
and
Meg Keil, MS, CNP, Director of Pediatric
Programs at NICHD, NIH in Bethesda, MD

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