Description

• Adrenal gland insufficiency from partial or complete destruction of the 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 (primary adrenocortical insufficiency) can be differentiated from secondary (pituitary failure) and tertiary (hypothalamic failure) causes 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; 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

• Autoimmune polyglandular syndrome (APS) type 2 genetics are complex. It is associated with adrenal insufficiency, type 1 diabetes, and Hashimoto disease. It is more common than APS type 1.
• APS type 1 is caused by mutations of the autoimmune regulator gene. Nearly all have the following triad: Adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis before adulthood.
• Adrenoleukodystrophy is an X-linked recessive disorder resulting in toxic accumulation of unoxidized long-chain fatty acids.
• Increased risk with cytotoxic T-lymphocyte antigen 4 (CTLA-4)

General Prevention

• No preventive measures known for Addison disease; focus on prevention of complications:
  • 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 insufficiency, autoimmune polyglandular syndromes 1 and 2, adrenoleukodystrophy
• Idiopathic

Commonly Associated Conditions

• Diabetes mellitus
• Graves disease
• Hashimoto's thyroiditis
• Hypoparathyroidism
• Hypercalcemia
• Ovarian failure
• Pernicious anemia
• Myasthenia gravis
• Vitiligo
• Chronic moniliasis
• Sarcoidosis
• Sjögren syndrome
• Chronic active hepatitis
• Schmidt syndrome

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 BP, 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 and Interpretation

• 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 BUN, creatinine, calcium, thyroid-stimulating hormone (TSH)
• Low serum aldosterone
• Hypoglycemia when fasting
• Metabolic acidosis
• Moderate neutropenia
• Eosinophilia
• Relative lymphocytosis
• Anemia, normochromic, normocytic

• 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:
  • 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

• Abdominal CT scan: Small adrenal glands in autoimmune adrenalitis; enlarged adrenal glands in infiltrative and hemorrhagic disorders
• Abdominal radiograph may show adrenal calcifications.
• Chest x-ray may show small heart size and/or calcification of cartilage.
• MRI 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].

• Atrophic adrenals in autoimmune adrenalitis
• Infiltrative and hemorrhagic disorders produce enlargement with destruction of the entire gland.

Differential Diagnosis

• Secondary adrenocortical insufficiency (pituitary failure):
  • Withdrawal of long-term corticosteroid use
  • Sheehan syndrome (postpartum necrosis of pituitary)
  • Empty sella syndrome
  • Radiation to pituitary
  • Pituitary adenomas, craniopharyngiomas
  • Infiltrative disorders of pituitary (sarcoidosis, hemochromatosis, amyloidosis, histiocytosis X)
• Tertiary adrenocortical insufficiency (hypothalamic failure):
  • Pituitary stalk transection
  • Trauma
  • Disruption of production of corticotropic-releasing factor
  • Hypothalamic tumors
• Other:
  • Myopathies
  • Syndrome of inappropriate antidiuretic hormone
  • Heavy-metal ingestion
  • Severe nutritional deficiencies
  • Sprue syndrome
  • Hyperparathyroidism
  • Neurofibromatosis
  • Peutz-Jegher syndrome
  • Porphyria cutanea tarda
  • Salt-losing nephritis
  • Bronchogenic carcinoma
  • Anorexia nervosa

Medication (Drugs)

• Chronic adrenal insufficiency:
  • Glucocorticoid supplementation:
    • Dosing: Hydrocortisone 15–20 mg (or therapeutic equivalent) PO each morning upon rising and 10 mg at 4–5 PM 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
  • Mineralocorticoid supplementation:
    • Dosing: Fludrocortisone 0.05–0.2 mg/d PO
  • May require salt supplementation
• Addisonian crisis:
  • Hydrocortisone 100 mg IV followed by 10 mg/hr infusion, or hydrocortisone 100 mg IV bolus q6–8h
  • IV glucose, saline, and plasma expanders
  • Fludrocortisone 0.05 mg/d PO (may not be required; high-dose hydrocortisone is an effective mineralocorticoid)
• Acute illnesses (fever, stress, minor trauma):
  • 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:
  • 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.

Addition of androgen therapy:

• Dehydroepiandrosterone (DHEA) 25–50 mg PO once daily may be considered in women to improve well-being and sexuality (4)[B].

Additional Treatment

Consider the 5 Ss for the management of adrenal crisis:

• Salt, sugar, steroids, support, and search for a precipitating illness (usually infection, trauma, recent surgery, or not taking prescribed replacement therapy)

In-Patient Considerations

Addisonian crisis:

• Airway, breathing, and circulation management
• Establish IV access; 5% dextrose and normal saline.
• Administer hydrocortisone 100 mg IV bolus q6–8h; replacement with fludrocortisone is not necessary (high-dose hydrocortisone is an effective mineralocorticoid).
• Correct electrolyte abnormalities.
• BP support for hypotension
• Antibiotics if infection suspected

• Presence of circulatory collapse, dehydration, hypotension, nausea, vomiting, hypoglycemia
• Intensive care unit admission for unstable cases

IV Fluids
IV saline containing 5% dextrose and plasma expanders

Follow-Up Recommendations

• 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

• National Adrenal Disease Foundation, Great Neck, NY 11021, (516) 487-4992 ( http://www.medhelp.org/nadf)
• Patient should wear or carry medical identification about the disease and the need for hydrocortisone or other replacement therapy.
• Instruct patient in self-administration 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

See Also

Algorithm: Adrenocortical Insufficiency

ICD-9

• 017.60 Tuberculosis of adrenal glands, unspecified
• 255.41 Glucocorticoid deficiency

ICD-10

• E27.1 Primary adrenocortical insufficiency
• A18.7 Tuberculosis of adrenal glands

SNOMED

• 363732003 Addison's disease (disorder)
• 186270000 Tuberculous Addison's disease
• 237760008 Addison's disease with adrenoleucodystrophy (disorder)