Shaun G.S. Grewal, MD
Gerald L. Andriole, MD, FACS
BASICS
DESCRIPTION
• Primary adrenal insufficiency
• Inadequate production of glucocorticoid and mineralocorticoid
– Differentiated from secondary (pituitary) and tertiary (hypothalamic) causes of adrenal causes of adrenocorticoid insufficiency in which mineralocorticoids are normally spared
ALERT
Acute adrenal insufficiency (Addisonian crisis):
• Life-threatening hypotensive shock.
• Most common cause is acute withdrawal of chronic steroid.
• Acute stress (ie, surgery) without an adequate stress dose of steroids.
EPIDEMIOLOGY
Incidence
• 4.7–6.2 per million in Western populations (1)
• Females more frequently affected than males
– TB most common cause in underdeveloped nations
– Autoimmune disorders most common cause in developed nations (90%)
Prevalence
• 93–140 per million (1)
– Mortality 0.3 per 100,000
RISK FACTORS
• Tuberculosis
• Autoimmune disease
• AIDS
• Immunosuppression
• Bilateral adrenal hemorrhage
• Bilateral adrenalectomy
• Drug induced
– Mitotane, aminoglutethimide, etomidate, ketoconazole, suramin, mifepristone
Genetics
• 40% of patients with a 1st-/2nd-degree relative with an associated disorder
• Isolated autoimmune adrenalitis
– HLA-DR3, CTLA 4
• APS type 1
– Adrenal insufficiency, hypoparathyroidism, chronic mucocutaneous candidiasis
– AIRE gene (21q22)
• APS type 2
– Adrenal insufficiency, Thyroid disease, Type I DM
– HLA-DR3, CTLA-4
• APS type 4
– Other autoimmune diseases
• Congenital adrenal hyperplasia
– 21β-hydroxylase (CYP21 mutation)
– 11β-hydroxylase (CYP 11B1 mutation)
– 17∂-hydroxylase (CYP17 mutation)
• Adrenoleukodystrophy (ALD)
– Demyelination of CNS
• Triple A syndrome (Allgrove)
– Alacrima, achalasia, neurologic impairment
PATHOPHYSIOLOGY
• Autoimmune disorders are the most common cause in developed nations (80–90%)
• Partial or complete T-cell mediated destruction of adrenal cells
– 90% of adrenal gland must be destroyed to cause insufficiency
– Decreased production of cortisol, aldosterone, and adrenal androgens
– Hypovolemia and prerenal azotemia cause orthostatic hypotension, dizziness, and lethargy
– Adrenal crisis mostly attributable to mineralocorticoid deficiency
– Pituitary compensation with increased ACTH
– ACTH and proopiomelanocortin-related peptides stimulate melanocytes causing hyperpigmentation
• Adrenal dysgenesis or hypoplasia
– AHC or Triple A syndrome
• Adrenal destruction
– APS1, APS2, APS4, ALD
– Infectious
TB, HIV, CMV, histoplasmosis, cryptococcus, coccidioidomycosis
– Adrenal hemorrhage
Sepsis
Disseminated intravascular coagulation
Anticoagulant therapy
– Bilateral adrenalectomy
• Adrenal infiltration
– Adrenal metastasis, primary adrenallymphoma, sarcoidosis, amyloidosis, hemochromatosis
• CAH (see Genetics)
ASSOCIATED CONDITIONS
• Autoimmune endocrine disorders
• Thyroid disorder (17%)
• Diabetes mellitus (12%)
• Gonadal dysfunction (12%)
GENERAL PREVENTION
No general prevention guidelines exist for prevention of primary hypoaldosteronism.
DIAGNOSIS
HISTORY
• Vague symptoms; requires high index of suspicion
– Fatigue, weight loss, anorexia, vomiting, GI complaints, abdominal pain, diarrhea, muscle aches, salt craving, hypotension, behavioral changes, headaches, sweating, depression, decreased libido, lethargy
– Acute adrenal insufficiency: Life-threatening hypotension, acute abdominal pain, vomiting, fevers
PHYSICAL EXAM
• Vitals: Orthostatic hypotension
• Weight loss
• Hyperpigmentation
• Pigmented buccal mucosa and nail beds
• Loss of axillary and pubic hair
• Vitiligo
• Goiter
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Electrolyte disturbances
– Classic triad: Hyponatremia, hyperkalemia, azotemia
– Hypercalcemia
– Lymphocytosis
– Hypoglycemia
– Metabolic acidosis
• Screening test
– Measure cortisol, ACTH
Low cortisol (<165 nmol/L)
Elevated ACTH (>45 pmol/L)
• Confirmation of abnormal screening test
– Short corticotropin test
250 μg ACTH
Serum cortisol at 0, 30, and 60 min
Peak cortisol <550 nmol/L diagnostic (2)
Imaging
• Routine imaging not recommended in cases of definite autoimmune adrenalitis
• CT or MRI in cases of suspected infection, malignancy, infiltration, hemorrhage
• Calcifications present in up to 50% with TB
Diagnostic Procedures/Surgery
No specific diagnostic procedures
Pathologic Findings
Atrophic adrenals in autoimmune adrenalitis
DIFFERENTIAL DIAGNOSIS
• Primary adrenal insufficiency (Addison disease)
• Secondary adrenal insufficiency (pituitary failure)
– No hyperpigmentation (lack of ACTH elevation)
– Etiologies include chronic steroids, panhypopituitarism, Sheehan syndrome (postpartum necrosis), brain trauma, pituitary apoplexy, pituitary surgery
• Tertiary adrenocortical insufficiency
TREATMENT
GENERAL MEASURES
• Acute adrenal insufficiency (addisonian crisis)
– 5 S’s:
Salt
Sugar
Steroids
Support
Search for precipitating cause
MEDICATION
First Line
• Corticosteroid replacement:
– Hydrocortisone 15–25 mg/d
BID dosing: 20 mg, 10 mg
TID dosing: 10 mg, 5 mg, 5 mg
Monitor body weight and signs/symptoms of over/under replacement
• Mineralocorticoid replacement:
– Fludrocortisone 0.05–0.20 mg/d
– Monitor blood pressure, peripheral edema, serum sodium, and potassium
• Major stress: Surgery, trauma, sepsis:
– IV hydrocortisone 100–300 mg/d (TID dosing) then taper
• Minor stress
– Increase steroid dose 2–3-fold then taper over several days
Second Line
• Dehydroepiandrosterone (DHEA) replacement
– 25–50 mg/d
– Impacts mood/feeling of well-being (3)
SURGERY/OTHER PROCEDURES
Stress dose steroids: 25–150 mg hydrocortisone or 5–30 mg methylprednisolone IV day of the procedure in addition to maintenance therapy; taper to the usual dose over 1–2 days.
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Salt loading prior to major stress recommended by some
• Future advances using long-acting hydrocortisone preparations to better mimic physiologic state
Complementary & Alternative Therapies
No established alternative therapies
ONGOING CARE
PROGNOSIS
• Adrenal crisis may be lethal.
• Recommended dosages for glucocorticoid and mineralocorticoid replacement rarely cause significant side effects; close monitoring is essential to prevent excess treatment.
COMPLICATIONS
• Side effects of excess steroid replacement:
– Weight gain, high BP, hyperglycemia, growth retardation, bruising, cardiovascular risks, gastric ulcers, poor wound healing, skin striae, osteoporosis
• Side effects of excess mineralocorticoid:
– Hypertension, bradycardia, hypernatremia, congestive heart failure, suppressed renin levels, growth retardation
• Acute withdrawal of chronic steroid replacement may precipitate acute adrenal crisis
• Must rule out or treat glucocorticoid deficiency prior to initiation of thyroxine for hypothyroidism, as this may precipitate adrenal crisis.
FOLLOW-UP
Patient Monitoring
• Medic-alert bracelet to be worn at all times
• Instruct patients on proper use of emergency hydrocortisone injections
• Monitor for signs of appropriate glucocorticoid and mineralocorticoid replacement
Patient Resources
• www.addisonsdisease.net
• www.addisonssupport.com
REFERENCES
1. Arlt W, Allolio B. Adrenal Insufficiency. Lancet. 2003;361:1881–1893.
2. Lvås K, Husebye E. Addison’s disease. Lancet. 2005;365:2058–2061.
3. Reisch N. Fine tuning for quality of life: 21st century approach to treatment of Addison’s disease. Endocrinol Metab Clin North Am. 2009;38:407–418.
ADDITIONAL READING
Chakera AJ. Addison disease in adults: Diagnosis and management. Am J Med. 2010;123:409–413.
See Also (Topic, Algorithm, Media)
• Addison Disease (Adrenocortical Insufficiency) Algorithm 
• Waterhouse–Friderichsen Syndrome
CODES
ICD9
255.41 Glucocorticoid deficiency
ICD10
E27.1 Primary adrenocortical insufficiency
CLINICAL/SURGICAL PEARLS
• Addisonian crisis: Is acute, life-threatening shock.
• 5 S’s for treatment of addisonian crisis
– Salt; Sugar; Steroids; Support; Search for precipitating cause.
• Classic triad: Hyponatremia, Hyperkalemia, Azotemia.
• Use “stress dose” steroids for patients with Addison disease undergoing surgical procedures.