The
adrenal glands are two pyramid-shaped glands that sit on top of each
kidney. Anatomically, the adrenal glands are composed of an outer
compartment called the adrenal cortex and an inner compartment called
the adrenal medulla. The adrenal medulla is regulated by the nervous
system and secretes three distinct hormones: epinephrine (adrenaline),
norepinephrine (noradrenaline), and dopamine. These are often referred
to as the “fight or flight” hormones. The adrenal cortex can be further
subdivided into three regions, each of which secretes its particular
steroid hormone. The adrenal cortex is primarily regulated by the
pituitary gland (an endocrine gland located in the brain) and releases
more than 50 steroid hormones. Among these are the hormones called
cortisol and aldosterone. Cortisol and aldosterone are considered
life-sustaining hormones because they regulate blood pressure, blood
sugar, and electrolyte balance, and also play an important role in our
body’s response to stress.
 |
| Adrenal glands |
ADRENAL INSUFFICIENCY:
Adrenal
insufficiency occurs when the adrenal glands produce inadequate amount
of one or more of the hormones listed above, such as cortisol and
aldosterone. Thomas Addison first described the symptoms and potentially
fatal consequences of absent adrenal function (termed adrenal
insufficiency or hypoadrenalism) in 1855. For this reason, adrenal
insufficiency is often called Addison’s disease. There are two types of
adrenal insufficiency:
1) Primary adrenal insufficiency:
In primary adrenal insufficiency, the adrenal glands are either damaged
or destroyed. This adrenal damage or destruction may occur from a
variety of causes, which will be discussed below
2) Secondary adrenal insufficiency:
In secondary adrenal insufficiency, the adrenal glands are actually
healthy, but fail to function properly because they are missing the
pituitary signals that stimulate them to release cortisol. The absent
pituitary signal is another hormone called ACTH (Adrenocorticotropic
Hormone). Any type of pituitary or hypothalamic disease can result in
loss of the ACTH signal, and in turn, lead to secondary adrenal
insufficiency. Because the adrenal hormone aldosterone is not primarily
regulated by pituitary ACTH, patients with secondary adrenal
insufficiency continue to produce aldosterone.
SYMPTOMS OF ADRENAL INSUFFICIENCY:
The
symptoms and signs of adrenal insufficiency are listed in the table
below; the most common symptoms are fatigue, weakness, poor appetite,
and weight loss. The number of + signs shown correlates with the
approximate frequency of the symptom/sign listed ( that is, more + signs
mean the symptom/sign is more likely to be present). Note, that certain
signs such as skin darkening or low potassium levels are primarily seen
in primary adrenal insufficiency, whereas many of the other
signs/symptoms overlap between the two types of adrenal insufficiency.
Approximate Frequency
Primary Secondary
Symptoms/Signs
Fatigue/Weakness ++++ ++++
Poor Appetite ++++ ++++
Weight Loss ++++ ++++
Nausea, Diarrhea +++ +++
Muscle, joint, abdominal pain ++ ++
Light-headedness upon standing ++ +
Low blood sodium level +++ +
Skin darkening +++
Low blood potassium level +++
As
you can see, the signs and symptoms of adrenal insufficiency are very
non-specific, meaning that they are common to many other disorders. Therefore,
a wise clinician should always consider adrenal insufficiency on the
differential diagnosis. The severity of the symptoms depends on the rate
and degree of loss of adrenal function. The presentation
of adrenal insufficiency (especially secondary adrenal insufficiency)
may be subtle and go undetected for many years until the stress of
another illness precipitates an adrenal crisis and unmasks the disease. President John F. Kennedy suffered from Addison’s disease. Historical
records indicate that while visiting London in 1947, Kennedy developed a
severe constellation of symptoms including nausea, vomiting, weakness
and low blood pressure. His condition was so dire at that time, that he
was given the last rites by the Roman Catholic Church. Of course Kennedy
survived that illness but was dependent on cortisol replacement by both
pills and injections.
CAUSES OF ADRENAL INSUFFICIENCY:
Primary Adrenal Insufficiency – Primary
adrenal insufficiency is an uncommon disorder, with a prevalence of
approximately 50 – 100 cases per one million adults.
The
leading cause of primary adrenal insufficiency in developed countries
is an autoimmune disorder in which the body’s immune system mounts an
attack against its own adrenal glands. Other immune disorders (such as
Hashimoto’s Thyroiditis, Type 1 diabetes mellitus, pernicious anemia, or
vitiligo) may also be present; resulting in a condition called
Autoimmune Polyendocrinopathy Syndrome (APS). Patients with adrenal
insufficiency as part of the APS are typically female. In
less-developed countries, tuberculosis and fungal infections of the
adrenal glands are much more common causes of adrenal insufficiency.
These infections are also more commonly seen in immunocompromised
persons such as those with HIV. HIV infection itself may also damage the
adrenal glands and result in adrenal insufficiency. Severe bacterial
infections in patients in the intensive care unit may lead to adrenal
hemorrhage (bleeding), particularly if the patient is receiving blood
thinners (this condition is called Waterhouse-Friderichsen Syndrome).
Certain medications (ketoconazole, etomidate) inhibit cortisol
production by the adrenal glands and may lead to adrenal insufficiency.
Certain cancers (especially lung cancer) may spread to the adrenal
glands and cause adrenal failure. Finally, congenital (present at birth)
and genetic disorders are rare causes of adrenal insufficiency.
Secondary Adrenal Insufficiency –
Secondary adrenal insufficiency is much more common than primary
adrenal insufficiency. The most frequent cause of secondary adrenal
insufficiency is an iatrogenic condition. Iatrogenic means that a health
care provider caused the condition unintentionally. This primarily
occurs when high-dose steroids are given to patients to treat certain
medical disorders, such as asthma, rheumatic disease, or other
inflammatory conditions. Through a process called feedback inhibition,
the high-dose steroids suppress pituitary production of ACTH. Since ACTH
is necessary to stimulate adrenal cortisol release, the lack of ACTH
will in turn lead to adrenal insufficiency. Such patients are at
particular risk for developing adrenal insufficiency if the high dose
steroids are stopped abruptly without a taper. Iatrogenic adrenal
insufficiency is generally reversible. By gradually tapering the dose of
steroids, pituitary production of ACTH may slowly return and secondary
adrenal insufficiency may resolve. The dose and duration of prior
exposure are the main determinants of how quickly this recovery occurs.
Other causes of secondary adrenal insufficiency include pituitary or
hypothalamic disorders, most commonly tumors. Pituitary radiation and
surgery may also result in secondary adrenal insufficiency.
DIAGNOSTIC TESTING:
Diagnostic
testing for adrenal insufficiency involves laboratory tests to find out
if the hormone levels are deficient and then further testing to
determine the cause. The first step in diagnostic testing is to confirm
that blood cortisol levels are low. Since cortisol levels fluctuate
during the day, it is important to have blood testing done in the early
morning. Cortisol levels are highest during the early morning. A morning
blood cortisol level of less than 3 mcg/dL is highly suspicious for
adrenal insufficiency. In most cases, an ACTH Stimulation Test (also
known as a Cortrosyn Simulation Test) is done to establish the
diagnosis, and can help distinguish primary from secondary adrenal
insufficiency. The ACTH Stimulation test involves measurement of blood
cortisol levels immediately before as well as 30 and 60 minutes after an
injection of 250 mcg of ACTH. ACTH is high in primary adrenal
insufficiency and tends to be low in secondary adrenal insufficiency.
This test is considered normal if the cortisol levels peaks above 18
mcg/dL after injection of ACTH. CT scan of the adrenal glands may also
be performed when the cause of primary adrenal insufficiency is unclear.
TREATMENT:
Treatment
of adrenal insufficiency involves the administration of adrenal
hormones to mimic the normal output by the adrenal glands. This is best
accomplished by giving hydrocortisone (Cortef) orally in two to three
divided doses each day. An alternative is to give a longer acting
steroid called prednisone. Since prednisone has a longer half life than
hydrocortisone, it may be administered once or twice per day. In recent
years, as we have come to better understand the normal output of the
adrenal glands, there is a trend to using a lower total daily dose of
hydrocortisone. Hydrocortisone replacement generally suffices in
patients with secondary adrenal insufficiency. However, as patients with
primary adrenal insufficiency are also deficient in aldosterone, they
must take a synthetic analog of aldosterone (called fludrocortisone)
along with hydrocortisone. Fludrocortisone is taken orally, once or
twice daily.
IN CASE OF AN EMERGENCY:
The
prognosis of adrenal insufficiency is generally quite good as long as
the patient remembers to take his or her medications consistently on a
daily basis and is under the close care of an endocrinologist. An
important point to remember is that the normal adrenal glands release
higher amounts of cortisol during periods of physical stress. The higher
amount of cortisol helps the body overcome the stressor. Any acute
illness, trauma, hospitalization, or surgery constitutes increase
physical stress. Under these circumstances, patients with adrenal insufficiency must double or triple their maintenance dose of hydrocortisone. This
is referred to as “stress-doses” of steroids. Once the stressor
improves and/or resolves, the dose of hydrocortisone is gradually weaned
back down to the maintenance dose. If the illness or “stressor”
includes vomiting and/or diarrhea, a person with adrenal insufficiency
must seek immediate medical care to receive hydrocortisone by injection
to ensure adequate absorption. A hydrocortisone emergency kit is also
available for emergency situations in which access to medical care may
be delayed. Patients with adrenal insufficiency must always wear an
alert bracelet or necklace that identifies them as having adrenal
insufficiency so that emergency personnel can provide stress doses of
steroids in the event of trauma, surgery, or hospitalization. Failure to
provide “stress doses” of steroid during critical illness may lead to
an adrenal crisis which may include loss of consciousness, shock or
other potentially fatal consequences.
REFERENCES:
Trainer
PJ and Besser GM, Addison’s Disease, in Comprehensive Clinical
Endocrinology, Besser GM and Thorner MO, Eds. Mosby Publishers, Third
Edition. 2002. Pages 203-212.
National Adrenal Disorders Foundation: www.NADF.US