Addison disease is caused by insufficient production of cortisol and aldosterone by the adrenal glands, usually due to an autoimmune process. It is treated with lifelong glucocorticoid and mineralocorticoid supplementation. Without treatment, Addison disease is fatal. Common symptoms include fatigue, low blood pressure, and hyperpigmentation. An acute adrenal crisis can be life-threatening and requires intravenous steroids, fluids, and treatment of any underlying illness.

1. Addison Disease
Basics
Description
• Insufficiency of the adrenal gland from primary disease
(partial or complete destruction of adrenal cells) with
inadequate secretion of glucocorticoids and
mineralocorticoids
• 80% of cases are caused by an autoimmune process, followed
by tuberculosis (TB), AIDS, systemic fungal infections, and
adrenoleukodystrophy.
• Addison disease can be differentiated from secondary
(pituitary failure) and tertiary (hypothalamic failure) causes
of adrenocortical insufficiency because mineralocorticoid
function usually remains intact in secondary and tertiary
causes.
• Addisonian (adrenal) crisis: Acute complication of adrenal
insufficiency (circulatory collapse, dehydration, hypotension,
nausea, vomiting, hypoglycemia); usually precipitated by an
acute physiologic stressor(s) such as surgery, illness,
exacerbation of comorbid process, and/or acute withdrawal
of long-term corticosteroid therapy
• System(s) affected: Endocrine/Metabolic
• Synonym(s): Adrenocortical insufficiency; Corticoadrenal
insufficiency; Primary adrenocortical insufficiency
Epidemiology
• Predominant age: All ages; usually 3rd–5th decade; mean
age at diagnosis in adults is 40 years
• Predominant sex: Females > Males (slight)
Incidence
0.6:100,000
Prevalence
4:100,000
Risk Factors
• ∼40% of patients have a 1st- or 2nd-degree relative with
associated disorders.
• Chronic steroid use, then experiencing severe infection,
trauma, or surgical procedures
Genetics

2. • Autoimmune polyglandular syndrome (APS) type 2 genetics
are complex. Associated with adrenal insufficiency, type 1
diabetes, and Hashimoto disease. More common than APS
type 1.
• APS type 1 caused by mutations of the autoimmune regulator
gene. Nearly all have the following triad: Adrenal
insufficiency, hypoparathyroidism, mucocutaneous
candidiasis before adulthood
• Adrenoleukodystrophy is an X-linked recessive disorder
resulting in toxic accumulation of unoxidized long-chain
fatty acids
• Frequent association with other autoimmune disorders
• Increased risk with cytotoxic T-lymphocyte antigen 4 (CTLA-
4)
General Prevention
• No preventive measures known for Addison disease; focus on
prevention of complications:
o Anticipate adrenal crisis and treat before symptoms
begin.
• Elective surgical procedures require upward adjustment in
steroid dose.
Pathophysiology
Destruction of the adrenal cortex resulting in deficiencies in
cortisol, aldosterone, and androgens
Etiology
• Autoimmune adrenal insufficiency (80% of cases in the US)
• Infectious causes: TB (most common infectious cause
worldwide), HIV (most common infectious cause in the US),
Waterhouse-Fredrickson syndrome, fungal disease
• Bilateral adrenal hemorrhage and infarction (for patients on
anticoagulants, 50% are in the therapeutic range)
• Antiphospholipid syndrome
• Lymphoma, Kaposi sarcoma, metastasis (lung, breast,
kidney, colon, melanoma); tumor must destroy 90% of gland
to produce hypofunction
• Drugs (ketoconazole, etomidate)
• Surgical adrenalectomy, radiation therapy
• Sarcoidosis, hemochromatosis, amyloidosis
• Congenital enzyme defects (deficiency of 21-hydroxylase
enzyme is most common), neonatal adrenal hypoplasia,
congenital adrenal hyperplasia, familial glucocorticoid

3. insufficiency, autoimmune polyglandular syndromes 1 and 2,
adrenoleukodystrophy
• Idiopathic
Commonly Associated Conditions
• Diabetes mellitus
• Graves disease
• Hashimoto thyroiditis
• Hypoparathyroidism
• Hypercalcemia
• Ovarian failure
• Pernicious anemia
• Myasthenia gravis
• Vitiligo
• Chronic moniliasis
• Sarcoidosis
• Sjögren syndrome
• Chronic active hepatitis
• Schmidt syndrome
Diagnosis
History
• Weakness, fatigue
• Dizziness
• Anorexia, nausea, vomiting
• Abdominal pain
• Chronic diarrhea
• Depression (60–80% of patients)
• Decreased cold tolerance
• Salt craving
Physical Exam
• Weight loss
• Low blood pressure, orthostatic hypotension
• Increased pigmentation (extensor surfaces, hand creases,
dental-gingival margins, buccal and vaginal mucosa, lips,
areola, pressure points, scars, “tanning,” freckles)
• Vitiligo
• Hair loss in females
Diagnostic Tests & Interpretation
Lab
Initial lab tests

4. • Basal plasma cortisol and adrenocorticotropic hormone
(ACTH) (low cortisol and high ACTH indicative of Addison
disease)
• Standard ACTH stimulation test: Cosyntropin 0.25 mg IV,
measure preinjection baseline, and 60-minute postinjection
cortisol levels (patients with Addison disease have low-to-
normal values that do not rise)
• Insulin-induced hypoglycemia test
• Metapyrone test
• Autoantibody tests: 21-hydroxylase (most common and
specific), 17-hydroxylase, 17-alpha-hydroxylase (may not be
associated), and adrenomedullin
• Circulating very-long-chain fatty acid levels if boy or young
man
• Low serum sodium
• Elevated serum potassium
• Elevated blood urea nitrogen, creatinine, calcium, thyroid-
stimulating hormone (TSH)
• Low serum aldosterone
• Hypoglycemia when fasted
• Metabolic acidosis
• Moderate neutropenia
• Eosinophilia
• Relative lymphocytosis
• Anemia, normochromic, normocytic
Follow-Up & Special Considerations
• Plasma ACTH levels do not correlate with treatment and
should not be used for routine monitoring of replacement
therapy (1)[C].
• TSH: Repeat when condition has stabilized:
o Thyroid hormone levels may normalize with the
treatment of Addison disease.
• Drugs that may alter lab results: Digitalis
• Disorders that may alter lab results: Diabetes
Imaging
Initial approach
• Abdominal computed tomography (CT) scan: Small adrenal
glands in autoimmune adrenalitis; enlarged adrenal glands
in infiltrative and hemorrhagic disorders
• Abdominal radiograph may show adrenal calcifications.

5. • Chest x-ray may show small heart size and/or calcification of
cartilage.
• Magnetic resonance imaging of pituitary and hypothalamus
if secondary or tertiary cause of adrenocortical insufficiency
is suspected.
Diagnostic Procedures/Surgery
CT-guided fine-needle biopsy of adrenal masses may identify
diagnoses (2)[C].
Pathological Findings
• Atrophic adrenals in autoimmune adrenalitis
• Infiltrative and hemorrhagic disorders produce enlargement
with destruction of the entire gland.
Differential Diagnosis
• Secondary adrenocortical insufficiency (pituitary failure):
o Withdrawal of long-term corticosteroid use
o Sheehan syndrome (postpartum necrosis of pituitary)
o Empty sella syndrome
o Radiation to pituitary
o Pituitary adenomas, craniopharyngiomas
o Infiltrative disorders of pituitary (sarcoidosis,
hemochromatosis, amyloidosis, histiocytosis X)
• Tertiary adrenocortical insufficiency (hypothalamic failure):
o Pituitary stalk transection
o Trauma
o Disruption of production of corticotropic-releasing
factor
o Hypothalamic tumors
• Other:
o Myopathies
o Syndrome of inappropriate antidiuretic hormone
o Heavy-metal ingestion
o Severe nutritional deficiencies
o Sprue syndrome
o Hyperparathyroidism
o Neurofibromatosis
o Peutz-Jeghers syndrome
o Porphyria cutanea tarda
o Salt-losing nephritis
o Bronchogenic carcinoma
o Anorexia nervosa
Treatment

6. Medication
First Line
• Chronic adrenal insufficiency:
o Glucocorticoid supplementation:
 Dosing: Hydrocortisone 15–20 mg (or
therapeutic equivalent) p.o. each morning upon
rising and 10 mg at 4–5 p.m. each afternoon (3)
[C]; dosage may vary and is usually lower in
children and the elderly
 Precautions: Hepatic disease, fluid disturbances,
immunosuppression, peptic ulcer disease,
pregnancy, osteoporosis
 Adverse reactions: Immunosuppression,
osteoporosis, gastric ulcers, depression,
hyperglycemia, weight gain, glaucoma
 Drug interactions: Concomitant use of rifampin,
phenytoin, or barbiturates
o Mineralocorticoid supplementation:
 Dosing: Fludrocortisone 0.05–0.2 mg p.o. per
day
o May require salt supplementation
• Addisonian crisis:
o Hydrocortisone 100 mg IV followed by 10 mg/h
infusion, or hydrocortisone 100 mg IV bolus q.6–8 h.
o IV glucose, saline, and plasma expanders
o Fludrocortisone 0.05 mg/d p.o. (may not be required;
high-dose hydrocortisone is an effective
mineralcorticoid)
• Acute illnesses (fever, stress, minor trauma):
o Double the patient's usual steroid dose, taper the dose
gradually over a week or more, and monitor vital signs
and serum sodium.
• Supplementation for surgical procedures:
o Administer hydrocortisone 25–150 mg or
methylprednisolone 5–30 mg IV on the day of the
procedure in addition to maintenance therapy; taper
gradually to the usual dose over 1–2 days.
Second Line
Addition of androgen therapy:
• Dehydroepiandrosterone (DHEA) 25–50 mg p.o. once daily
may be considered in women to improve well-being and
sexuality (4)[B].

7. Additional Treatment
General Measures
Consider the 5 S's for the management of adrenal crisis:
• Salt, sugar, steroids, support, search for a precipitating
illness (usually infection, trauma, recent surgery, or not
taking prescribed replacement therapy)
In-Patient Considerations
Initial Stabilization
Addisonian crisis:
• Airway, breathing, and circulation management
• Establish IV access; 5% dextrose and normal saline
• Administer hydrocortisone 100 mg IV bolus q.6–8h.;
replacement with fludrocortisone is not necessary (high-dose
hydrocortisone is an effective mineralcorticoid)
• Correct electrolyte abnormalities.
• Blood pressure (BP) support for hypotension
• Antibiotics if infection suspected
Admission Criteria
• Presence of circulatory collapse, dehydration, hypotension,
nausea, vomiting, hypoglycemia
• Intensive care unit admission for unstable cases
IV Fluids
Intravenous saline containing 5% dextrose and plasma expanders
Discharge Criteria
Normal laboratory and stable vital signs
Ongoing Care
Follow-Up Recommendations
Patient Monitoring
• Verify adequacy of therapy: Normal BP, serum electrolytes,
plasma renin, and fasting blood glucose level
• Periodically assess for the development of long-term
complications of corticosteroid use, including screening for
osteoporosis, gastric ulcers, depression, and glaucoma
• Lifelong medical supervision for signs of adequate therapy
and avoidance of overdose
Diet
Maintain water, sodium, and potassium balance.
Patient Education
• For patient education materials, contact: National Adrenal
Disease Foundation, 505 Northern Blvd., Suite 200, Great

8. Neck, NY 11021, (516) 487–4992
(http://www.medhelp.org/nadf)
• Patient should wear or carry medical identification with
information about the disease and the need for
hydrocortisone or other replacement therapy.
• Instruct patient in self-administering of parenteral
hydrocortisone for emergency situations.
Prognosis
Requires lifetime treatment: Life expectancy approximates normal
with adequate replacement therapy; without treatment, the disease
is 100% lethal.
Complications
• Hyperpyrexia
• Psychotic reactions
• Complications from underlying disease
• Over- or underuse of steroid treatment
• Hyperkalemic paralysis (rare)
• Addisonian crisis
References
1. Nieman LK, Chanco Turner ML. Addison's disease. Clin
Dermatol. 2006 Jul-Aug;24:276–80
2. Oelkers W. Adrenal insufficiency. N Engl J Med.
1996;335:1206–12
3. Coursin DB, Wood KE. Corticosteroid supplementation for
adrenal insufficiency. JAMA. 2002;287:236–40
4. Arlt W, Callies F, van Vlijmen JC et al. Dehydroepiandrosterone
replacement in women with adrenal insufficiency. N Engl J Med.
1999;341:1013–20
Additional Reading
See Also (Topic, Algorithm, Electronic Media Element)
Algorithm: Adrenocortical Insufficiency
Codes
ICD9
• 255.41 Glucocorticoid deficiency
• 017.60 Tuberculosis of adrenal glands, unspecified
examination
Snomed
• 363732003 Addison disease (disorder)
• 186270000 Tuberculous Addison disease (disorder)
Clinical Pearls

9. • 80% of cases are caused by an autoimmune process, and the
average age of diagnosis in adults is 40 years.
• Consider the 5 S's for the management of Addison disease:
Salt, sugar, steroids, support, and search for an underlying
cause.
• The goal of steroid replacement therapy should be to use the
lowest dose that alleviates patient symptoms while
preventing adverse drug events.
• Plasma ACTH levels do not correlate with treatment and
should not be used for routine monitoring for efficacy of
replacement therapy.
• Long-term use of steroids predisposes patients to the
development of osteoporosis; screen annually and encourage
calcium and vitamin D supplementation.
Thank you