Addison Disease: Early Detection

and Treatment Principles

AARON MICHELS, MD, University of Colorado–Denver, Aurora, Colorado
NICOLE MICHELS, PhD, Rocky Vista University, Parker, Colorado

Primary adrenal insufficiency, or Addison disease, has many causes, the most common of which is autoimmune adre-
nalitis. Autoimmune adrenalitis results from destruction of the adrenal cortex, which leads to deficiencies in glucocor-
ticoids, mineralocorticoids, and adrenal androgens. In the United States and Western Europe, the estimated prevalence
of Addison disease is one in 20,000 persons; therefore, a high clinical suspicion is needed to avoid misdiagnosing a
life-threatening adrenal crisis (i.e., shock, hypotension, and volume depletion). The clinical manifestations before an
adrenal crisis are subtle and can include hyperpigmentation, fatigue, anorexia, orthostasis, nausea, muscle and joint
pain, and salt craving. Cortisol levels decrease and adrenocorticotropic hormone levels increase. When clinically sus-
pected, patients should undergo a cosyntropin stimulation test to confirm the diagnosis. Treatment of primary adrenal
insufficiency requires replacement of mineralocorticoids and glucocorticoids. During times of stress (e.g., illness, inva-
sive surgical procedures), stress-dose glucocorticoids are required because destruction of the adrenal glands prevents
an adequate physiologic response. Management of primary adrenal insufficiency or autoimmune adrenalitis requires
vigilance for concomitant autoimmune diseases; up to 50% of patients develop another autoimmune disorder during
their lifetime. (Am Fam Physician. 2014;89(7):563-568. Copyright © 2014 American Academy of Family Physicians.)

M
CME This clinical content ore than 150 years ago, disease develops, individuals lose adrenocor-
conforms to AAFP criteria Thomas Addison described tical function over a period of years. In the
for continuing medical
education (CME). See
a group of patients with ane- first three stages, the human leukocyte anti-
CME Quiz Questions on mia and diseased adrenal gen genes confer genetic risk; an unknown
page 515. glands at autopsy, a condition now known precipitating event initiates antiadrenal auto-
Author disclosure: No rel- as primary adrenal insufficiency. Autoim- immunity; and 21-hydroxylase antibodies are
evant financial affiliations. mune adrenalitis is the most common cause produced, which predict future disease. The
Patient information:
of primary adrenal insufficiency, or Addi- production of these antibodies can precede
▲

A handout on this topic son disease, in the United States. Less com- symptom onset by years to decades, and they
is available at http:// mon causes include infection, hemorrhage, are present in more than 90% of recent-onset
familydoctor.org/ metastatic cancer, medication use, and cases.2,4-7 In the fourth stage, overt adrenal
familydoctor/en/diseases-
conditions/addisons- adrenoleukodystrophy. insufficiency develops. One of the first meta-
disease.html. Autoimmune adrenalitis is a disorder in bolic abnormalities to occur is an increase in
which the adrenal cortex is destroyed, result- plasma renin level, followed by the sequential
ing in the loss of mineralocorticoid, gluco- development of other abnormalities, includ-
corticoid, and adrenal androgen hormone ing a decreased response to adrenocortico-
production. Addison disease can be part of tropic hormone (ACTH) stimulation in the
the autoimmune polyglandular syndromes fifth stage. If symptoms of adrenal insuf-
(type 1 and 2), or it may present as an iso- ficiency are present but go undiagnosed, an
lated disorder.1 This article focuses on the addisonian crisis can occur.
diagnosis and treatment of Addison disease
as an isolated disorder, with a focus on the Clinical Diagnosis
pathophysiology and treatment consider- Because the estimated prevalence of Addison
ations of autoimmune adrenalitis. disease is one in 20,000 persons in the United
States and Western Europe, a high clinical
Pathogenesis suspicion is needed to avoid misdiagnosing
Autoimmune adrenalitis can be divided into a life-threatening adrenal crisis.8 Signs and
stages of progression2,3 (Table 13). As the symptoms can be subtle and nonspecific.

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Addison Disease
SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

Addison disease, or primary adrenal insufficiency, is diagnosed after confirming an elevated ACTH level and C 12, 22
an inability to stimulate cortisol levels with a cosyntropin stimulation test.
Addison disease should be treated with a glucocorticoid (i.e., daily prednisone, twice daily hydrocortisone, or C 16-20
daily dexamethasone). Treatment should be titrated to the lowest dose that relieves symptoms.
Addison disease should be treated with a mineralocorticoid (i.e., daily fludrocortisone). Treatment should be C 21, 22
titrated to keep the plasma renin activity in the upper normal range.
Dehydroepiandrosterone (DHEA) therapy may improve depression symptoms and health-related quality of B 23
life in women.
Physicians should remain vigilant for the development of concomitant autoimmune disorders in patients C 8, 28-34
with Addison disease.

ACTH = adrenocorticotropic hormone.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

Patients may experience fatigue, weakness, weight loss, stimulation of the corticotrophs in the anterior pituitary.
and gastrointestinal upset9 (Table 210). Symptoms are Specifically, it results from cross-reactivity between the
gradual and worsen over a period of years, making early ACTH produced by the corticotrophs and the melano-
diagnosis difficult.10 The symptoms relate to the degree cortin 1 receptor on keratinocytes. Hyperpigmentation
of cortisol, mineralocorticoid, and adrenal androgen is usually generalized over the entire body and can be
deficiency at the time of presentation. Addison disease found in palmar creases, buccal mucosa, vermilion bor-
is usually diagnosed after a significant stress or illness der of the lips, and around scars and nipples. It is not a
unmasks cortisol and mineralocorticoid deficiency, pre- feature of secondary adrenal insufficiency because of the
senting as shock, hypotension, and volume depletion lack of increased ACTH in these patients.
(adrenal or addisonian crisis).11 Cortisol and aldosterone
deficiencies contribute to hypotension, orthostasis, and Diagnosis
shock; however, adrenal crisis is more likely to occur in METABOLIC TESTS
primary adrenal insufficiency compared with secondary The goal of laboratory testing is to document a low cortisol
adrenal insufficiency. level and determine whether the adrenal insufficiency is
Hyperpigmentation is the physical finding most char- primary or secondary, as outlined in Figure 1. Low serum
acteristic of Addison disease, arising from continual cortisol levels at 8 a.m. (less than 3 mcg per dL [83 nmol
per L]) suggest adrenal insufficiency, as do
low serum sodium and high serum potassium
Table 1. Development Stages of Autoimmune Adrenalitis levels.12 Hyponatremia can be attributed to
cortisol and mineralocorticoid deficiencies,
Stage Symptoms Comments
whereas hyperkalemia is attributed solely to
1. Genetic risk None HLA-B8, -DR3, and -DR4 genes a lack of mineralocorticoids.
confer risk Because the adrenal hormones are gradu-
2. P recipitating event None Possible environmental trigger ally lost over years to decades, the levels
starts antiadrenal vary. One of the first indications that there
autoimmunity
is adrenal cortex dysfunction is an elevated
3. 21-hydroxylase None Antibodies appear before
antibodies present disease onset in 90% of cases plasma renin level.13 A rise in ACTH levels
4. Metabolic Fatigue, anorexia, Increased ACTH and decreased is concomitant with the loss of adrenal hor-
decompensation nausea, hyper­ 8 a.m. cortisol levels; high mones. Yearly monitoring of ACTH levels in
pigmentation clinical suspicion needed for at-risk individuals shows that measurements
diagnosis
greater than 50 pg per mL (11 pmol per L),
5. Decreased Hypotension and Severe symptoms can be life-
response to ACTH shock (addisonian threatening
which exceed the upper limit of normal, are
stimulation crisis) indicative of cortisol deficiency.7 A cosyntro-
pin stimulation test is the first-line test for
ACTH = adrenocorticotropic hormone. diagnosing adrenal insufficiency. The serum
Information from reference 3. cortisol, plasma ACTH, plasma aldosterone,
and plasma renin levels should be measured

564  American Family Physician www.aafp.org/afp Volume 89, Number 7 ◆ April 1, 2014
 Addison Disease

before administering 250 mcg of ACTH. At 30 and

Table 2. Signs and Symptoms of Addison Disease 60 minutes after intravenous ACTH administration, the
serum cortisol level should be measured again. A normal
Sign or symptom Prevalence (%) response occurs with peak cortisol levels greater than
18 to 20 mcg per dL (497 to 552 nmol per L); a smaller or
Anorexia 100
absent response is diagnostic for adrenal insufficiency.14,15
Weakness, fatigue 100
Hyperpigmentation 94 IMMUNOLOGIC TESTS
Gastrointestinal symptoms (e.g., nausea, vomit­ 92
ing, abdominal pain, constipation, diarrhea) Measurement of 21-hydroxylase antibody levels helps
Hypotension (systolic blood pressure < 110 ~90 discern the cause of Addison disease. The 21-hydroxylase
mm Hg) enzyme is necessary for cortisol synthesis in the adre-
Salt cravings 16 nal cortex; antibodies directed against the enzyme are
Postural dizziness 12 specific for autoimmune adrenalitis and are detectable
Vitiligo 10 to 20 before symptom onset.
Muscle or joint pain ~10
IMAGING
Information from reference 10.
Radiographic imaging is also helpful in determining the
cause of Addison disease, but it is relatively nonspecific
in patients with autoimmune destruction. It is important
to make a biochemical diagnosis of adrenal insufficiency
Diagnosis of Adrenal Insufficiency
Patient presents with signs or
before radiographic imaging. Computed tomography
symptoms of adrenal insufficiency demonstrates small adrenal glands in patients with auto-
immune adrenal destruction. In other causes of Addison
disease, computed tomography may show hemorrhage,
Order basic metabolic panel and measure­
ment of 8 a.m. serum cortisol level
calcification associated with tuberculosis infection, or
masses in the adrenal gland. However, computed tomog-
raphy is not necessary to diagnose adrenal insufficiency.

Results inconsistent Low cortisol level Treatment

with adrenal Normal to high potassium level HORMONE THERAPY
insufficiency
Low to normal sodium level Treatment for Addison disease consists of lifelong hor-
mone therapy with glucocorticoids and mineralocorti-
Consider other
Perform cosyntropin stimulation test: coids16 (Table 3). To date, there is no therapy available to
diagnoses
measure basal ACTH level before stop the underlying immune destruction of the adrenal
admin­istering intravenous ACTH (250 cortex. Generally, glucocorticoid replacement includes
mcg); measure cortisol level again after
30 and 60 minutes after administration oral prednisone or hydrocortisone.17 Prednisone can
be taken once daily, whereas hydrocortisone is divided
into two or three doses per day.18-20 Mineralocorticoids
are replaced with fludrocortisone at a dose sufficient to
Normal Low cortisol level Low cortisol level keep the plasma renin level in the upper limit of the
cosyntropin High ACTH level Low ACTH level
test result
normal range.21,22
Men who have Addison disease do not need replace-
Primary adrenal Secondary adrenal ment with androgens because their testes are able to pro-
Consider other insufficiency insufficiency duce adequate testosterone levels; however, women can
diagnoses
benefit from androgen replacement because the adrenals
are the main source of androgen production in women.
To identify etiology:
Measure 21-hydroxylase antibody level
A meta-analysis of 10 randomized placebo-controlled
Perform computed tomography of adrenal gland trials found that dehydroepiandrosterone (DHEA) sup-
plementation resulted in small improvements in health-
Figure 1. Algorithm for the diagnosis of adrenal insuffi- related quality of life and depression in women with
ciency. (ACTH = adrenocorticotropic hormone.) adrenal insufficiency.23

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Addison Disease

Table 3. Medications for the Treatment of Addison Disease

Medication Dosage Comments Monitoring

Glucocorticoids
Prednisone 3 to 5 mg once daily Use stress doses for illness, surgical Symptoms of adrenal insufficiency;
procedures, and hospitalization low to normal plasma
Hydrocortisone 15 to 25 mg divided Use stress doses for illness, surgical adrenocorticotropic hormone
into two or three procedures, and hospitalization levels indicate over-replacement
doses per day
Dexamethasone 0.5 mg once daily Use intramuscular dose for emergencies
and when unable to tolerate oral intake
Mineralocorticoid
Fludrocortisone 0.05 to 0.2 mg once Dosage may need to increase to 0.2 mg per Blood pressure; serum sodium and
daily day in the summer because of salt loss potassium levels; plasma renin
from perspiration activity in the upper normal range
Androgen
Dehydroepiandrosterone 25 to 50 mg once Available as an over-the-counter Libido, mood, and sense of well-
(DHEA) daily supplement; can improve mood and being
quality of life in women

STRESS DOSING OF GLUCOCORTICOIDS because the thyroid hormone increases the hepatic clear-
Patients should be counseled about the need for stress- ance of cortisol. In addition, patients with a new diagno-
dose glucocorticoids for illnesses and before surgical sis can have a reversible increase in thyroid-stimulating
procedures because destruction of the adrenal glands hormone levels because glucocorticoids inhibit secre-
prevents an adequate physiologic response to stress.24 tion.25,26 Glucocorticoid replacement can result in the
There are many expert recommendations for stress dos- normalization of thyroid-stimulating hormone levels
ing of steroids based on the degree of stress; clinical trials less than 30 mIU per L. In individuals with type 1 diabe-
comparing different approaches are lacking in the liter- tes mellitus, unexplained hypoglycemia and decreasing
ature. In our practice, we use a stress-dose strategy for insulin requirements may be the initial signs of Addison
outpatient procedures (e.g., colonoscopy, upper endos- disease.27
copy) and invasive dental procedures (e.g., root canal)
TREATMENT OF CONFIRMED ADDISON DISEASE
that patients can implement easily. This involves a dose
of glucocorticoids three times the maintenance dose the Patients with Addison disease should be treated in con-
day of the procedure and two days after (i.e., three times junction with an endocrinologist and be monitored on a
three rule for stress-dose glucocorticoids). regular basis for appropriate hormone therapy (Table 3).
For minor illnesses such as influenza or viral gastroen- Glucocorticoid doses should be titrated to the lowest
teritis, the patient can take three times the steroid dose tolerated dose that controls symptoms to minimize the
during the illness and resume normal dosing after resolu- adverse effects of excess glucocorticoid. It is important to
tion of symptoms. Patients should also have an injectable instruct patients to learn the proper guidelines for stress
form of glucocorticoid (intramuscular dexamethasone) dosing of glucocorticoids, to have an injectable form of
available in cases of nausea, vomiting, or other situa- glucocorticoid available, and to wear an adrenal insuf-
tions when oral intake is not possible. Mineralocorticoid ficiency medical alert identification.
replacement generally does not need to be changed for Approximately 50% of persons with Addison disease
illness or procedures. However, the dose may need to be caused by autoimmune adrenalitis develop another
adjusted in the summer months when there is salt loss autoimmune disorder during their lifetime, necessitat-
from excessive perspiration. ing lifelong vigilance for associated autoimmune con-
ditions.28,29 Table 4 outlines concomitant autoimmune
TREATMENT CAVEATS disorders and their relative prevalence, as well as appro-
Thyroid hormone therapy in persons with undiag- priate autoantibodies and metabolic tests for patients
nosed Addison disease may precipitate an adrenal crisis with Addison disease who develop signs and symptoms

566  American Family Physician www.aafp.org/afp Volume 89, Number 7 ◆ April 1, 2014
 Addison Disease

Table 4. Autoimmune Disorders Occurring with Addison Disease

Disease Lifetime prevalence (%) Appropriate diagnostic tests

Autoimmune thyroid disease (Hashimoto 22 Thyroid-stimulating hormone, thyroid peroxidase antibody,

disease or Graves disease) 8,28-32 and thyroid-stimulating immunoglobulin levels
Celiac disease33 12 Tissue transglutaminase antibody level
Type 1 diabetes mellitus8,28-30,32 11 A1C, fasting blood glucose, and islet autoantibody levels
Hypoparathyroidism8,28-30,32 10 Calcium and parathyroid hormone levels
Primary ovarian insufficiency34 10 Follicle-stimulating hormone level
Pernicious anemia8,28,29 5 Complete blood count, vitamin B12 level, and parietal cell
antibody level
Primary gonadal failure (testes) 29 2 Testosterone, follicle-stimulating hormone, and luteinizing
hormone levels
None8,28-34 50 —

NOTE: Data compiled from multiple studies across different populations.

Information from references 8, and 28 through 34.

of one of these disorders.8,28-34 Of note, 10% of women

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