Addison's Disease

is an uncommon disease, caused by partial or complete failure of the outer layer of the adrenal
glands (the adrenal cortex).

Description of Addison's Disease

The adrenal gland produces hormones that control many body functions. In Addison's disease,
there is a chronic deficiency of cortisol, aldosterone and adrenal androgens (hormones made in
the adrenal glands). When the body is deficient in these hormones, the result can be high levels
of potassium and low levels of salt, causing an electrolyte imbalance in the body.

The Importance Of Cortisol

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, 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, slow the immune system's
inflammatory response, balance the effect of insulin in breaking down sugar for energy and
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. One of the pituitary's main functions is to
secrete ACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands.

Causes and Risk Factors of Addison's Disease

Failure to produce adequate amounts 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 an inadequate secretion of ACTH by the pituitary gland (secondary adrenal
insufficiency). Autoimmune destruction of the adrenals is the most common form of Addison�s
disease in the U.S. (80 percent of all cases). It may occur alone or as part of a syndrome. Other
causes include adrenal hemorrhage (bleeding), tuberculosis and genetic disorders.

Symptoms of Addison's Disease

The symptoms of adrenal insufficiency usually begin gradually. Worsening chronic 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 all cases. Blood pressure is low and falls
further when standing, causing dizziness or fainting.
Skin changes are also 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 and pressure points, such as the elbows, knees, knuckles, toes, lips
and mucous membranes.

Addison's disease can cause irritability and depression. Because of salt loss, craving of salty
foods is also common. Hypoglycemia (or low blood sugar) is more severe in children than in
adults. In women, menstrual periods may become irregular or stop completely.

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 25 percent of all patients, symptoms do not appear until 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.

Diagnosis of Addison's Disease

Diagnosis is based on medical history, symptoms, physical examination and blood tests (often
cortisol and ACTH).

Treatment of Addison's Disease

Treatment includes a combination of glucocorticoids and mineralocorticoids to replace the

adrenal insufficiency. Hydrocortisone and fludrocortisone are commonly prescribed. In addition,
all infections must be treated aggressively. The dose of glucocorticoids is raised in case of
trauma, surgery, stressful diagnostic procedures or other forms of stress. Patients should wear a
medical alert bracelet stating

Laboratory Studies

 A quick review of the clinical presentation, physical examination findings, and laboratory
findings (when available) quickly heightens the index of suspicion and possibly leads to
more appropriate tests and diagnosis. A high index of suspicion is necessary for
diagnosis.
 The diagnosis of adrenocortical insufficiency rests on the assessment of the functional
capacity of the adrenal cortex to synthesize cortisol. This is accomplished primarily by
use of the rapid ACTH stimulation test (Cortrosyn, cosyntropin, or Synacthen).
o ACTH, through complex mechanisms, activates cholesterol esterase enzymes and
leads to the release of free cholesterol from cholesterol esters. It also activates the
20,22-desmolase enzyme, which catalyzes the rate-limiting step in adrenal
 steroidogenesis and increases the NADPH (nicotinamide adenine dinucleotide
phosphate) levels necessary for the various hydroxylation steps in steroidogenesis.
o Within 15-30 minutes of ACTH infusion, the normal adrenal cortex releases 2-5
times its basal plasma cortisol output.
o Although ACTH stimulation is not normally the major stimulus for aldosterone
production, it increases aldosterone production to peak levels within 30 minutes.
This response, however, is affected by dietary sodium intake.
o An increase in the plasma cortisol and aldosterone levels above basal levels after
ACTH injection reflects the functional integrity of the adrenal cortex.
 Performing the rapid adrenocorticotrophic hormone test
o Blood is drawn in 2 separate tubes for baseline cortisol and aldosterone values.
o Synthetic ACTH (1-24 amino acid sequence) in a dose of 250 mcg (0.25 mg) is
given IM or IV. Smaller doses of synthetic ACTH, as low as 1 mcg, have been
used with accuracy approaching the standard test. Proponents of this modified test
argue that a dose of 1 mcg or lower is more physiologic, whereas the 250-mcg
dose is pharmacologic. However, the modified test is more sensitive only for the
30-minute samples, not the 60-minute samples.
o Thirty or 60 minutes after the ACTH injection, 2 more blood samples are drawn;
one for cortisol and one for aldosterone. No significant reason exists to draw both
the 30-minute and 60-minute samples because the sensitivity of the 30-minute
value for accurate diagnosis is well documented. The baseline and 30-minute
samples usually are adequate to establish the diagnosis.
 Interpreting the rapid adrenocorticotrophic hormone test
o Two criteria are necessary for diagnosis: (1) an increase in the baseline cortisol
value of 7 mcg/dL or more and (2) the value must rise to 20 mcg/dL or more in 30
or 60 minutes, establishing normal adrenal glucocorticoid function.
o A low aldosterone value of less than 5 ng/100 mL that fails to double or increase
by at least 4 ng/100 mL 30 minutes after ACTH administration denotes abnormal
mineralocorticoid function of the adrenal cortex.
o The 30-minute aldosterone value is more sensitive than the 60-minute value
because aldosterone levels actually have been shown to decrease in the 60-minute
sample.
o The absolute 30- or 60-minute cortisol value carries more significance than the
incremental value, especially in patients who may be in great stress and at their
maximal adrenal output. These patients may not show a significant increase in
cortisol output with ACTH stimulation.
o A normal 30- or 60-minute rapid ACTH test excludes Addison disease but may
not adequately exclude mild impairment of the hypothalamic pituitary adrenal
axis in secondary adrenal insufficiency.
o In patients with Addison disease, both cortisol and aldosterone show minimal or
no change in response to ACTH, even with prolonged ACTH stimulation tests
lasting 24-48 hours.
o When the results of the rapid ACTH test are equivocal and do not meet the 2
criteria mentioned above, further testing might be required to distinguish Addison
 disease from secondary adrenocortical insufficiency. Plasma ACTH values and
prolonged ACTH stimulation tests may be useful in making this distinction.
o ACTH levels often are elevated to higher than 250 pg/mL in patients with
Addison disease. However, ACTH is unstable in plasma, and specimen collection
and storage may require special attention. The specimen should be collected in
iced anticoagulated plastic containers and frozen immediately.
o Importantly, note that ACTH levels also may be high in patients recovering from
steroid-induced secondary adrenocortical insufficiency and in patients with
ACTH-refractory syndromes.
o ACTH-inducing tests such as metyrapone stimulation and insulin-induced
hypoglycemia, which may be useful in the evaluation of some cases of secondary
adrenocortical insufficiency, have no role in the diagnosis of Addison disease and
may in fact be lethal to the patient with Addison disease.
 In acute adrenal crisis, where treatment should not be delayed in order to do the tests, a
blood sample for a random plasma cortisol level should be drawn prior to starting
hydrocortisone replacement.
o A random plasma cortisol value of 25 mcg/dL or greater effectively excludes
adrenal insufficiency of any kind. However, a random cortisol value in patients
who are acutely ill should be interpreted with caution and in correlation with the
circumstances of each individual patient. Random cortisol levels should also be
interpreted cautiously in critically ill patients with hypoproteinemia (serum
albumin <2.5 g/dL). Approximately 40% of these patients will have baseline and
cosyntropin-stimulated cortisol levels below the reference range even though the
patients have normal adrenal function (as evidenced by the measurement of free
cortisol levels). This phenomenon is because more than 90% of circulating
cortisol in human serum is protein bound.
o Cortisol is known to be elevated by stress, but exactly how high it should rise to
constitute a normal response in times of severe stress is not known.
o An abnormal test result should prompt a proper evaluation of the hypothalamic
pituitary adrenal axis after the patient's condition improves before committing a
patient to lifelong steroid replacement.
o In order to perform the ACTH stimulation test in this situation, the patient should
be switched to dexamethasone and then tested 24-36 hours later. Dexamethasone
does not interfere with the cortisol assay, as does hydrocortisone or prednisone.
However, dexamethasone may interfere with interpretation of the random cortisol
value drawn after dexamethasone already has been initiated. Dexamethasone also
does not have any mineralocorticoid activity, which may be needed in patients
with Addison disease.
 Other laboratory tests
o Comprehensive metabolic panel
 The most prominent findings are hyponatremia, hyperkalemia, and a mild
non–anion-gap metabolic acidosis due to the loss of the sodium-retaining
and potassium and hydrogen ion-secreting action of aldosterone.
 Urinary and sweat sodium also may be elevated.
  The most consistent finding is elevated blood urea nitrogen (BUN) and
creatinine due to the hypovolemia, a decreased glomerular filtration rate,
and a decreased renal plasma flow.
 Hypercalcemia, the cause of which is not well understood, may be present
in a small percentage of patients. However, hypocalcemia could occur in
patients with Addison disease accompanied by idiopathic
hypoparathyroidism.
 Hypoglycemia may be present in fasted patients, or it may occur
spontaneously. It is caused by the increased peripheral utilization of
glucose and increased insulin sensitivity. It is more prominent in children
and in patients with secondary adrenocortical insufficiency.
 Liver function tests may reveal a glucocorticoid-responsive liver
dysfunction.
o CBC count
 CBC count may reveal a normocytic normochromic anemia, which, upon
initial presentation, may be masked by dehydration and
hemoconcentration. Relative lymphocytosis and eosinophilia may be
present.
 All of these findings are responsive to glucocorticoid replacement.  
o Thyroid-stimulating hormone
 Increased thyroid-stimulating hormone (TSH), with or without low
thyroxine, with or without associated thyroid autoantibodies, and with or
without symptoms of hypothyroidism, may occur in patients with Addison
disease and in patients with secondary adrenocortical insufficiency due to
isolated ACTH deficiency. These findings may be slowly reversible with
cortisol replacement.
 In the setting of both adrenocortical insufficiency and hypothyroidism that
requires treatment, corticosteroids should be given before thyroid hormone
replacement to avoid precipitating an acute adrenal crisis.
 Autoantibody testing - Thyroid autoantibodies, specifically antithyroglobulin (anti-Tg)
and antimicrosomal or antithyroid peroxidase (anti-TPO) antibodies, and/or adrenal
autoantibodies may be present.
 Prolactin testing
o Modest hyperprolactinemia has been reported in cases of Addison disease and
also in secondary adrenocortical insufficiency. It is responsive to glucocorticoid
replacement.
o The cause of the hyperprolactinemia is thought to be the hyperresponsiveness of
the lactotroph to thyrotropin-releasing hormone (TRH) in the absence of the
steroid-induced or steroid-enhanced hypothalamic dopaminergic tone.

Imaging Studies

 Chest radiograph
o The chest radiogram may be normal but often reveals a small heart.
o Stigmata of earlier infection or current evidence of TB or fungal infection may be
present when this is the cause of Addison disease.
  CT scan
o Abdominal CT scan may be normal but may show bilateral enlargement of the
adrenal glands in patients with Addison disease because of TB, fungal infections,
adrenal hemorrhage, or infiltrating diseases involving the adrenal glands.
o In Addison disease due to TB or histoplasmosis, evidence of calcification
involving both adrenal glands may be present.
o In idiopathic autoimmune Addison disease, the adrenal glands usually are
atrophic.

Other Tests

 ECG may show low-voltage QRS tracing with nonspecific ST-T wave changes and/or
changes due to hyperkalemia. These changes are reversible with glucocorticoid
replacement.
 Sputum examination, examination of gastric washings for acid-fast and alcohol-fast
bacilli, and a Mantoux or purified protein derivative (PPD) skin test may be needed if TB
is thought to be the cause.

Histologic Findings

In cases due to idiopathic autoimmune adrenocortical atrophy, the adrenal glands usually are
atrophic, with marked lymphocytic infiltration and fibrosis of the adrenal capsule. The adrenal
medulla is spared.

In cases due to TB, the adrenal glands may be enlarged and contain caseating granulomas.
Diffuse calcification may be evident, and the adrenal medulla usually is involved

In patients with AIDS, the adrenal glands may show necrotizing inflammation, hemorrhage, and
infarction.