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Cushing's disease or syndrome may be confused with pseudo Cushing's.
The symptoms of pseudo Cushing's may be caused by alcoholism, depression,
or by taking steroid medications over long periods of time. Steroid
medications may be used to treat conditions like rheumatoid arthritis,
asthma, vasculitis, lupus, and a variety of other autoimmune disorders.
Cortisol is produced by the adrenal glands, which are located
just above the kidneys. The adrenal glands are endocrine organs
that secrete hormones into the blood stream. They are regulated
by the pituitary gland to produce cortisol as needed. Higher amounts
are needed in the morning and through out the early day and needed
less in evening hours. This 24-hour rhythm is called a circadian
rhythm. Extra cortisol is naturally produced during an illness or
any type of physical or psychological stress. Cortisol belongs to
a class of hormones called glucocorticoids, which affect almost
every organ and tissue in the body. Cortisol helps regulate blood
pressure, the immune system, blood sugar, and helps regulate the
metabolism of proteins, carbohydrates, and fats.
Symptoms of Cushing's
Disease
The symptoms caused by excessive cortisol secretion may
vary from person to person. Many of the symptoms listed below can
be attributed to numerous other diseases if viewed separately. However,
several of these symptoms seen together could suggest testing for
Cushing's disease.
Moon Face - The face becomes round and may look
flushed.
High Blood Pressure- Almost all patients with Cushing's
have high blood pressure because of complex actions of cortisol
in the kidney and on blood vessels.
High Cholesterol - The high blood pressure interacts
with high cholesterol levels that are often seen in patients with
Cushing's to increase the risk of
atherosclerosis.
High Blood Sugar - Diabetes is common in patients
with Cushing's. As many as 3% of uncontrolled diabetics may actually
have Cushing's. The disorder is due to the effects of cortisol on
insulin action and handling of glucose.
Truncal Obesity - An accumulation of fat around
the abdomen, neck and collar bone.
Muscle Weakness - Legs and arms lose muscle mass
and appear thin in comparison to trunk.
Backaches - Pain in neck shoulders and back are
common in Cushing's.
Buffalo Hump - Fat can accumulate at the back
of the neck and between the shoulder blades.
Skin Changes - Skin may become thin, fragile and
easily bruised. Acne may develop in all ages.
Straie - Bluish-red stretch marks may form on
abdomen, breast, thighs, upper arms and buttocks.
Weak Immune System - Poor wound healing and increased
chances of infections.
Menstrual Periods - Periods may be irregular or
cease.
Labedo - Lack of sexual desire for men & women.
Men may have difficulty maintaining an erection.
Hirsutism - Abnormal hair growth on face.
Balding - Hair at temples and on the scalp may
become thin.
Emotional Disturbances - Mood swings, depression,
irritability, confusion, and poor memory.
Extreme Fatigue - Weakness and fatigue during
the day and difficulty sleeping at night.
Osteoporosis - Fragile thinning bones. Bones loose
their density and may fracture or break.
Kidney Stones - These are often the first manifestation
of Cushing's syndrome. The calcium that comes from the bones leaks
through the kidneys into the urine and can crystallize causing calcium
stones.
Some patients have sustained high cortisol levels without the symptoms
of Cushing’s syndrome or disease. These high cortisol levels
may be compensating for the body’s resistance to cortisol’s
effects. This rare syndrome of cortisol resistance is a genetic
condition that causes hypertension and chronic androgen excess.
Polycystic ovarian syndrome is another condition that may share
some of the same symptoms as Cushing’s. Patients with polycystic
ovarian syndrome have menstrual disturbances, facial hair, weight
gain, high blood pressure and high cholesterol. Polycystic ovarian
syndrome does not cause abnormally high cortisol levels.
Diagnosis
The first step in diagnosis is to determine if the symptoms
are due to excess cortisol production. Demonstrating cortisol excess
is somewhat complicated because cortisol production in a normal
individual varies from highest in the morning to lowest at night.
Cortisol can also vary according to a person’s health, stress
level, and activity level. Therefore, simply measuring the quantity
of circulating cortisol and ACTH in a patient's bloodstream in one
blood test is not enough information to diagnose Cushing's Disease.
Your endocrinologist may want to start with a few tests that will
require your help and ability to follow directions precisely. One
test is a 24-hour free cortisol urine collection. You will use a
kit to collect urine for 24 hours. This urine is analyzed in a laboratory
to determine the quantity of cortisol in the urine. The Urine Free
Cortisol test has a sensitivity of about 95%, but has the disadvantage
of relying on patient management for proper collection
The 24-hour urine free cortisol (UFC) collection can be used with
the Dexamethasone Suppression Test. Dexamethasone is a steroid drug
taken by mouth. It is very similar to cortisol that the adrenal
glands produce. In a healthy patient who has taken Dexamethasone,
the endocrine system will recognize that plenty of the steroid resembling
cortisol is in the blood and will turn off cortisol production.
The results in healthy individuals will be low urine cortisol levels.
In a patient with Cushing’s the dexamethasone does not suppress
excess cortisol production and the amount of cortisol in the urine
will be high.
One variation of the Dexamethasone tests is done with CRH (cortisol
releasing hormone). This variation of the test is useful to identify
patients who have Cushing's from those who do not.
Another test that can be used with the 24 hour (UFC) is a salivary
cortisol screening test. It is a diagnostic tool that can be performed
by the patient to obtain late evening cortisol levels measured from
saliva. It is convenient method to use when obtaining PM cortisol
levels (before bedtime). The test is done in the convenience of
one’s home with out causing stress which could alter PM cortisol
levels. This test can be repeated several days and evenings in a
row. Salivary cortisol screening test is also helpful in diagnosing
intermittent Cushing’s.
The next step is to determine if the source of excess cortisol
is from an ACTH producing pituitary tumor, adrenal tumor or an ectopic
tumor. There are several variations of the Dexamethasone test used
to gain additional information. Many of these variations use different
doses of dexamethasone administered at night or repeatedly at various
intervals. The serum cortisol and urine cortisol is measured during
the test.
Imaging techniques
Magnetic Resonance Imaging
An MRI is used to look at the pituitary and CT scans to
look at adrenal glands after a firm diagnosis of elevated cortisol
and ACTH. The availability of diagnostic and imaging techniques
has improved detection of pituitary microadenoma’s (a tumor
under 10mm in size). Pituitary tumors that produce ACTH are usually
small and 30 % are so small that they are not easily detected by
MRI.
Treatment
For patients with Cushing’s disease
caused by a pituitary tumor, surgery to remove the tumor is generally
recommended. Surgery or radiotherapy may be used to treat pituitary
adenomas. The aim of treatment is to cure the hypercortisolism and
to eliminate any tumor that threatens the individual's health, while
minimizing the chance of endocrine deficiency or long-term dependence
on medications.
Surgery
Pituitary surgery should be
done by a neurosurgeon who has experience removing pituitary tumors
using the transphenoidal approach (under the upper lip) or transnasal
(through the nose) approach. The neurosurgeon you choose should
routinely perform more than twenty pituitary surgeries’ per
year. Because pituitary surgery can cause ACTH levels to drop too
low, some patients will require short-term treatment with a cortisol-like
medication after surgery. Patients who need adrenal surgery may
also require steroid replacement. You should take these medications
as prescribed by your physician without interruption. If the entire
pituitary gland or adrenal gland has been removed, the patient will
need to take all hormone replacements for the rest of his or her
life.
Following Pituitary Surgery
The following symptoms may occur after surgery and should be discussed
with doctor. Sinus Infection, Worsening headache, fever, chills,
yellowish green nasal discharge, and neck stiffness may all signify
an infectious process.
Hyponatremia (low blood sodium levels). Some patients develop disorders
of salt and water metabolism following pituitary surgery. Headache,
nausea, vomiting, confusion, impaired concentration, and muscle
aches might be due to hyponatremia (low blood sodium levels). This
disorder typically occurs 7 to 10 days after surgery and is more
common in patients who have had surgery for Cushing’s disease.
If you develop these symptoms, contact your Endocrinologist and
Neurosurgeon immediately.
Diabetes Insipidus
Excessive urination, thirst, and the need to ingest large
quantities of fluids might be related to the onset of diabetes insipidus
or diabetes mellitus. These disorders put you at risk for dehydration.
The symptoms require urgent evaluation and determination of the
underlying cause so that appropriate treatment may be given. If
these symptoms develop, contact your physicians immediately.
Adrenal Insufficiency
Patients who are dependent on cortisol replacement medications
should consult their doctor immediately when experiencing flu like
symptom. Cortisol replacement dosages may need to be increased during
a fever, illness, or trauma.
If a person has to take steroid replacement (hydrocortisone, prednisone,
dexamethasone), he or she should wear a Medic Alert bracelet or
necklace, which identifies the need for steroid treatment in case
of emergency. The medical ID should indicate deficiency.
Follow
up
In general, the first postoperative follow-up visit will
be scheduled a few weeks after surgery. If problems develop prior
to your appointment, you will be asked to return to your neurosurgeon
as soon as possible. Your return appointments will be scheduled
according to your needs. Lifelong follow-up is necessary. You should
ensure that you receive appropriate follow-up by physicians knowledgeable
in diagnosing and managing pituitary disorders.
Medical Therapy
For patients who continue to have excess pituitary production of
ACTH following surgery, medications can be helpful along with other
therapies. Although there is no medication to control Cushing’s
disease, a few drugs can be used in reducing the levels of cortisol.
Drugs such as ketoconazole, metyrapone, and mitotane, trilostane,
and aminoglutethimide have been used with varying success. These
drugs may be given after surgery (sometimes along with radiation
treatments).
Radiation Therapy
Radiation to the pituitary is not the first line of treatment
for most pituitary tumors. Radiation may be used for patients who
cannot undergo surgery, or when there is tumor remaining after surgery.
Radiation does not produce an immediate effect to lower excessive
hormone production or shrink the tumor. There are different methods
of delivering radiation to the pituitary gland. The decision as
to which type of radiation to administer must be made only after
a careful review of the MRI scan to assess the size and location
of the residual tumor.
Conventional Radiation - Pituitary radiation such
as conventional (fractionated) radiation may take several years
to be effective. Conventional (fractionated) radiation refers to
delivery of a small amount of radiation daily for 4 to 5 weeks.
Stereotactic Radiation - Stereotactic radiation
refers to delivery of a precisely focused beam of radiation, usually
as one treatment. A large tumor near the optic chiasm (eye nerves)
is not suitable for stereotactic radiation because of the intensity
of the single treatment and risk of damage to vision. In general,
stereotactic radiation is reserved for a small residual tumor, which
is not near the optic chiasm.
Side Effects - The most common side effect of
radiation is loss of pituitary function. This may occur within a
year or many years after treatment. One study reported that 50%
of patients treated with conventional radiation developed deficiency
of one or more pituitary hormones within 2 years of treatment. Although
development of a pituitary hormone deficiency is not desirable,
hormone replacement therapy is available. An uncommon side effect
is damage to vision. These risks must be weighed against the risk
of tumor re-growth.
Gamma Knife - Gamma Knife radiosurgery is a method
for delivering focused radiation therapy to pituitary tumors. Using
Gamma Knife for a pituitary tumor is most often used as secondary
therapy after surgery. The size and location of the residual tumor
are the limiting factors in selecting a patient for this treatment.
It can be used in cases where the entire tumor was not successfully
removed. Gamma Knife radiation is focused at the residual tumor.
If the tumor is not seen on the MRI scan the entire pituitary gland
is usually targeted for treatment. Gamma Knife treatment may also
be appropriate for patients who have an initial remission after
surgery and then develop a recurrence of excessive hormone secretion.
Gamma Knife radiation treatment is usually administered as a single
treatment which requires most of one day. If the tumor remaining
after surgery is too close to the optic chiasm (eye nerves) or is
too large, Gamma Knife is not advisable because of the risk of damage
to vision.
Recovery
Cushing's affects every system of the body. It may take
a long time for the body to reverse the effects of excess cortisol.
With Cushing's muscles become thin and weak. It may take several
months after surgery for the body to rebuild muscle and reduce excess
weight. Usually about 9 to 12 months after surgery a patient will
see markable improvements. Some improvements can be seen soon after
surgery. Because of the long recovery time, a patient may want to
keep a journal and note all of the small improvements. Taking one
day at a time and looking for the good things in each day can make
this a time of personal growth. When the recovery process seems
to stand still it is helpful to read the journal and remember how
much improvement you have made. Patience, perseverance, and positive
attitude will improve recovery.
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