Addison's disease is a rare endocrine or
hormonal disorder that affects about 1 in 100,000 people
"
Addison's disease occurs when the adrenal
glands do not produce enough of the hormone cortisol and in some
cases, the hormone aldosterone. "
Addison's disease is a rare endocrine or hormonal disorder
that affects about 1 in 100,000 people. It occurs in all age groups
and afflicts men and women equally. The disease is characterized
by weight loss, muscle weakness, fatigue, low blood pressure,
and sometimes darkening of the skin in both exposed and nonexposed
parts of the body.
Addison's disease occurs when the adrenal glands do not produce
enough of the hormone cortisol and in some cases, the hormone
aldosterone. For this reason, the disease is sometimes called
chronic adrenal insufficiency, or hypocortisolism.
Cortisol is normally produced by the adrenal glands,
located just above the kidneys. It belongs to a class of hormones
called glucocorticoids, which affect almost every organ and tissue
in the body. Scientists think that cortisol has possibly hundreds
of effects in the body. Cortisol's most important job is to help
the body respond to stress.
Among its other vital tasks, cortisol:
- helps maintain blood pressure and cardiovascular function
- helps slow the immune system's inflammatory response
- helps balance the effects of insulin in breaking down sugar
for energy
- and helps regulate the metabolism of proteins, carbohydrates,
and fats
Because cortisol is so vital to health, the amount of cortisol
produced by the adrenals is precisely balanced. Like many other
hormones, cortisol is regulated by the brain's hypothalamus and
the pituitary gland, a bean-sized organ at the base of the brain.
First, the hypothalamus sends "releasing hormones" to the pituitary
gland. The pituitary responds by secreting other hormones that
regulate growth, thyroid and adrenal function, and sex hormones
such as estrogen and testosterone. One of the pituitary's main
functions is to secrete ACTH (adrenocorticotropin), a hormone
that stimulates the adrenal glands. When the adrenals receive
the pituitary's signal in the form of ACTH, they respond by producing
cortisol. Completing the cycle, cortisol then signals the pituitary
to lower secretion of ACTH.
Aldosterone belongs to a class of hormones called mineralocorticoids,
also produced by the adrenal glands. It helps maintain blood pressure
and water and salt balance in the body by helping the kidney retain
sodium and excrete potassium. When aldosterone production falls
too low, the kidneys are not able to regulate salt and water balance,
causing blood volume and blood pressure to drop.
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Causes
Failure to produce adequate levels of cortisol, or adrenal insufficiency,
can occur for different reasons. The problem may be due to a disorder
of the adrenal glands themselves (primary adrenal insufficiency)
or to inadequate secretion of ACTH by the pituitary gland (secondary
adrenal insufficiency).
Primary Adrenal Insufficiency
Most cases of Addison's disease are caused by the gradual destruction
of the adrenal cortex, the outer layer of the adrenal glands,
by the body's own immune system. About 70 percent of reported
cases of Addison's disease are due to autoimmune disorders, in
which the immune system makes antibodies that attack the body's
own tissues or organs and slowly destroy them. Adrenal insufficiency
occurs when at least 90 percent of the adrenal cortex has been
destroyed. As a result, often both glucocorticoid and mineralocorticoid
hormones are lacking. Sometimes only the adrenal gland is affected,
as in idiopathic adrenal insufficiency; sometimes other glands
also are affected, as in the polyendocrine deficiency syndrome.
The polyendocrine deficiency syndrome is classified into
two separate forms, referred to as type I and type II. Type I
occurs in children, and adrenal insufficiency may be accompanied
by underactive parathyroid glands, slow sexual development, pernicious
anemia, chronic candida infections, chronic active hepatitis,
and, in very rare cases, hair loss. Type II, often called Schmidt's
syndrome, usually afflicts young adults. Features of type II may
include an underactive thyroid gland, slow sexual development,
and diabetes mellitus. About 10 percent of patients with type
II have vitiligo, or loss of pigment, on areas of the skin. Scientists
think that the polyendocrine deficiency syndrome is inherited
because frequently more than one family member tends to have one
or more endocrine deficiencies.
Tuberculosis (TB) accounts for about 20 percent of cases
of primary adrenal insufficiency in developed countries. When
adrenal insufficiency was first identified by Dr. Thomas Addison
in 1849, TB was found at autopsy in 70 to 90 percent of cases.
As the treatment for TB improved, however, the incidence of adrenal
insufficiency due to TB of the adrenal glands has greatly decreased.
Less common causes of primary adrenal insufficiency are chronic
infections, mainly fungal infections; cancer cells spreading from
other parts of the body to the adrenal glands; amyloidosis; and
surgical removal of the adrenal glands. Each of these causes is
discussed in more detail below.
---------------------------
Secondary Adrenal Insufficiency
This form of Addison's disease can be traced to a lack of ACTH,
which causes a drop in the adrenal glands' production of cortisol
but not aldosterone. A temporary form of secondary adrenal insufficiency
may occur when a person who has been receiving a glucocorticoid
hormone such as prednisone for a long time abruptly stops or interrupts
taking the medication. Glucocorticoid hormones, which are often
used to treat inflammatory illnesses like rheumatoid arthritis,
asthma, or ulcerative colitis, block the release of both corticotropin-releasing
hormone (CRH) and ACTH. Normally, CRH instructs the pituitary
gland to release ACTH. If CRH levels drop, the pituitary is not
stimulated to release ACTH, and the adrenals then fail to secrete
sufficient levels of cortisol.
Another cause of secondary adrenal insufficiency is the
surgical removal of benign, or noncancerous, ACTH-producing tumors
of the pituitary gland (Cushing's disease). In this case, the
source of ACTH is suddenly removed, and replacement hormone must
be taken until normal ACTH and cortisol production resumes. Less
commonly, adrenal insufficiency occurs when the pituitary gland
either decreases in size or stops producing ACTH. This can result
from tumors or infections of the area, loss of blood flow to the
pituitary, radiation for the treatment of pituitary tumors, or
surgical removal of parts of the hypothalamus or the pituitary
gland during neurosurgery of these areas.
---------------------------
Symptoms
The symptoms of adrenal insufficiency usually begin gradually.
Chronic, worsening fatigue and muscle weakness, loss of appetite,
and weight loss are characteristic of the disease. Nausea, vomiting,
and diarrhea occur in about 50 percent of cases. Blood pressure
is low and falls further when standing, causing dizziness or fainting.
Skin changes also are common in Addison's disease, with areas
of hyperpigmentation, or dark tanning, covering exposed and nonexposed
parts of the body. This darkening of the skin is most visible
on scars; skin folds; pressure points such as the elbows, knees,
knuckles, and toes; lips; and mucous membranes.
Addison's disease can cause irritability and depression.
Because of salt loss, craving of salty foods also is common. Hypoglycemia,
or low blood sugar, is more severe in children than in adults.
In women, menstrual periods may become irregular or stop.
Because the symptoms progress slowly, they are usually ignored
until a stressful event like an illness or an accident causes
them to become worse. This is called an addisonian crisis, or
acute adrenal insufficiency. In most patients, symptoms are severe
enough to seek medical treatment before a crisis occurs. However,
in about 25 percent of patients, symptoms first appear during
an addisonian crisis.
Symptoms of an addisonian crisis include sudden penetrating
pain in the lower back, abdomen, or legs; severe vomiting and
diarrhea, followed by dehydration; low blood pressure; and loss
of consciousness. Left untreated, an addisonian crisis can be
fatal.
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Diagnosis
In its early stages, adrenal insufficiency can be difficult
to diagnose. A review of a patient's medical history based on
the symptoms, especially the dark tanning of the skin, will lead
a doctor to suspect
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Addison's disease
A diagnosis of Addison's disease is made by biochemical laboratory
tests. The aim of these tests is first to determine whether there
are insufficient levels of cortisol and then to establish the
cause. X-ray exams of the adrenal and pituitary glands also are
useful in helping to establish the cause.
---------------------------
ACTH Stimulation Test
This is the most specific test for diagnosing Addison's disease.
In this test, blood and/or urine cortisol levels are measured
before and after a synthetic form of ACTH is given by injection.
In the so called short, or rapid, ACTH test, cortisol measurement
in blood is repeated 30 to 60 minutes after an intravenous ACTH
injection. The normal response after an injection of ACTH is a
rise in blood and urine cortisol levels. Patients with either
form of adrenal insufficiency respond poorly or do not respond
at all.
When the response to the short ACTH test is abnormal,
a "long" ACTH stimulation test is required to determine the cause
of adrenal insufficiency. In this test, synthetic ACTH is injected
either intravenously or intramuscularly over a 48- to 72-hour
period, and blood and/or urine cortisol are measured the day before
and during the 2 to 3 days of the injection. Patients with primary
adrenal insufficiency do not produce cortisol during the 48- to
72-hour period; however, patients with secondary adrenal insufficiency
have adequate responses to the test on the second or third day.
In patients suspected of having an addisonian crisis,
the doctor must begin treatment with injections of salt, fluids,
and glucocorticoid hormones immediately. Although a reliable diagnosis
is not possible while the patient is being treated, measurement
of blood ACTH and cortisol during the crisis and before glucocorticoids
are given is sufficient to make the diagnosis. Once the crisis
is controlled and medication has been stopped, the doctor will
delay further testing for up to 1 month to obtain an accurate
diagnosis.
---------------------------
Insulin-Induced Hypoglycemia Test
A reliable test to determine how the hypothalamus and pituitary
and adrenal glands respond to stress is the insulin-induced hypoglycemia
test. In this test, blood is drawn to measure the blood glucose
and cortisol levels, followed by an injection of fast-acting insulin.
Blood glucose and cortisol levels are measured again at 30, 45,
and 90 minutes after the insulin injection. The normal response
is for blood glucose levels to fall and cortisol levels to rise.
---------------------------
Other Tests
Once a diagnosis of primary adrenal insufficiency has been made,
x-ray exams of the abdomen may be taken to see if the adrenals
have any signs of calcium deposits. Calcium deposits may indicate
TB. A tuberculin skin test also may be used.
If secondary adrenal insufficiency is the cause, doctors may
use different imaging tools to reveal the size and shape of the
pituitary gland. The most common is the CT scan, which produces
a series of x-ray pictures giving a cross-sectional image of a
body part. The function of the pituitary and its ability to produce
other hormones also are tested.
---------------------------
Treatment
Treatment of Addison's disease involves replacing, or substituting,
the hormones that the adrenal glands are not making. Cortisol
is replaced orally with hydrocortisone tablets, a synthetic glucocorticoid,
taken once or twice a day. If aldosterone is also deficient, it
is replaced with oral doses of a mineralocorticoid, called fludrocortisone
acetate (Florinef)), which is taken once a day. Patients receiving
aldosterone replacement therapy are usually advised by a doctor
to increase their salt intake. Because patients with secondary
adrenal insufficiency normally maintain aldosterone production,
they do not require aldosterone replacement therapy. The doses
of each of these medications are adjusted to meet the needs of
individual patients.
During an addisonian crisis, low blood pressure, low
blood sugar, and high levels of potassium can be life threatening.
Standard therapy involves intravenous injections of hydrocortisone,
saline (salt water), and dextrose (sugar). This treatment usually
brings rapid improvement. When the patient can take fluids and
medications by mouth, the amount of hydrocortisone is decreased
until a maintenance dose is achieved. If aldosterone is deficient,
maintenance therapy also includes oral doses of fludrocortisone
acetate.
---------------------------
Special Problems
Surgery
Patients with chronic adrenal insufficiency who need surgery
with general anesthesia are treated with injections of hydrocortisone
and saline. Injections begin on the evening before surgery and
continue until the patient is fully awake and able to take medication
by mouth. The dosage is adjusted until the maintenance dosage
given before surgery is reached.
Pregnancy
Women with primary adrenal insufficiency who become pregnant
are treated with standard replacement therapy. If nausea and vomiting
in early pregnancy interfere with oral medication, injections
of the hormone may be necessary. During delivery, treatment is
similar to that of patients needing surgery; following delivery,
the dose is gradually tapered and the usual maintenance doses
of hydrocortisone and fludrocortisone acetate by mouth are not
reached until about 10 days after childbirth.
---------------------------
Patient Education
A person who has adrenal insufficiency should always carry identification
stating his or her condition in case of an emergency. The card
should alert emergency personnel about the need to inject 100
mg of cortisol if its bearer is found severely injured or unable
to answer questions. The card should also include the doctor's
name and telephone number and the name and telephone number of
the nearest relative to be notified. When traveling, it is important
to have a needle, syringe, and an injectable form of cortisol
for emergencies. A person with Addison's disease also should know
how to increase medication during periods of stress or mild upper
respiratory infections. Immediate medical attention is needed
when severe infections or vomiting or diarrhea occur. These conditions
can precipitate an addisonian crisis. A patient who is vomiting
may require injections of hydrocortisone.
----------------------------
It is very helpful for persons with medical problems to wear
a descriptive warning bracelet or neck chain to alert emergency
personnel. Bracelets and neck chains can be obtained from:
Medic Alert Foundation International
2323 Colorado
Turlock, California 95381
(209) 668-3333
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Suggested Reading
The following materials can be found in medical libraries, many
college and university libraries, and through interlibrary loan
in most public libraries.
Wingert, Terence D. and Mulrow, Patrick J., "Chronic Adrenal
Insufficiency," in Current Diagnosis, edited by Rex B. Conn. Philadelphia,
MI.B. Saunders Company, 1985, pp 860-863.
Bravo, Emmanuel L., "Adrenocortical Insufficiency," in Conn's
Current Therapy, edited by Robert E. Rakel. Philadelphia, W.B.
Saunders Company, 1987, pp 493-495.
Bondy, Philip K., "Disorders of the Adrenal Cortex," in Williams
Textbook of Endocrinology, seventh edition, edited by Jean D.
Wilson and Daniel W. Foster. Philadelphia, R.B. Saunders Company,
1985, pp 844-858.
Loriaux, D. Lynn and Cutler, Gordon B., "Diseases of the Adrenal
Glands," in Clinical Endocrinology, edited by Peter O. Kohler.
New York, lohn Wiley & Sons, 1986, pp 208-215.
Williams, Gordon H. and Dluhy, Robert G., "Diseases of the Adrenal
Cortex," in Harnson's Principles of Internal Medicine, 11th edition,
edited by Eugene Braunwald, Kurt J. Isselbacher, Robert G. Petersdorf,
Jean D. Wilson, Joseph B. Martin, and Anthony S. Fauci. New York,
McGraw-Hill Book Company, 1987, pp 1769-1772.
Baxter, John D. and Tyrrell, 1. Blake, "The Adrenal Cortex,"
in Endocrinolegy and Metabolism, second edition, edited by Philip
Felig,, John D. Baxter, Arthur E. Broadus, and Lawrence A. Frohman.
New York, McGraw-Hill Book Company, 1987, pp 581-599.
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Other Resources
National Adrenal Disease Foundation
505 Northern Boulevard, Suite 200
Great Neck, New York 11021
(516) 487-4992
---------------------------
This e-pub was written by Eileen K. Corrigan of NIDDK's Office
of Health Research Reports. The draft was reviewed by Dr. George
P Chrousos, National Institute of Child Health and Human Development,
Dr. Judith Fradkin, National Institute of Diabetes and Digestive
and Kidney Diseases, and by Dr. Richard Horton, University of
Southern California Medical Center.
June 2000
related
info
*What
is Addison's disease? - Endocrinology at the Jefferson Health
System
Endocrinology
- Addison's Disease - Vanderbilt University Medical Center
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