Addison's disease (primary adrenal failure)

Introduction

Addison's disease (primary adrenal failure) is caused by deficiency of cortisol with or without deficiency of aldosterone.

Etiology

• autoimmune adrenalitis* (also see Complications: below)
• infections of the adrenal gland
  • tuberculosis
  • mycosis, especially histoplasmosis
  • AIDS-associated
    • cytomegalovirus
    • Mycobacterium avium
    • cryptococcus
    • primary HIV
  • bacterial infection
• hemorrhagic adrenal infarction
  • precipitating factors
    • postoperative period
    • coagulation disorders
    • hypercoagulable states
    • sepsis
  • symptoms
    • abdominal or flank pain
    • fever
• amyloidosis
• hemochromatosis
• metastatic neoplasm
  • lymphoma
  • leukemia
  • lung cancer
  • breast cancer
  • rarely cause enough adrenal destruction to result in adrenal insufficiency
• bilateral adrenalectomy
• sarcoidosis
• adrenoleukodystrophy
• see adrenal insufficiency for secondary adrenal insufficiency

* most common cause of primary adrenal insufficiency

Pathology

• autoimmune adrenalitis destroys all layers of the adrenal cortex
  • 90% of adrenal must be destroyed before adrenal failure occurs
• secretion of cortisol, aldosterone & DHEA affected
• glucocorticoid deficiency
  • decreased cardiac stroke volume
  • heart rate increases
  • cardiac output declines
  • vasopressin is released
  • free water retention
  • inhibition of catecholamine activity
  • diminished peripheral vascular resistance
  • hypotension
• aldosterone deficiency
  • urinary Na+ loss
  • diminished urinary K+ excretion
• DHEA-sulfate deficiency

Clinical manifestations

• general manifestations of glucocorticoid deficiency
  • weakness & fatigue
  • weight loss
  • diffuse musculoskeletal pain, arthralgia
  • orthostatic hypotension
  • dehydration
  • auricular calcifications
  • symptoms of hypoglycemia
  • low-grade fever
• manifestations of mineralocorticoid deficiency
  • salt craving
  • orthostatic hypotension
  • syncope
• manifestations of androgen deficiency in women (DHEA-sulfate deficiency)
  • decreased body hair, decreased pubic & axillary hair
  • amenorrhea
• skin manifestations
  • mottled skin pigmentation (hyperpigmentation* due to ACTH secretion)
    • buccal mucosa (Caucasians)
    • lips, gingival margins, buccal mucosa
    • elbows, knees, knuckles, palmar creases, scars
    • vagina, rectum
  • vitiligo suggests autoimmune etiology
• gastrointestinal
  • anorexia or aversion to food
  • nausea & vomiting
  • abdominal pain
  • diarrhea
• psychiatric manifestations
  • depression
  • apathy
  • confusion
  • psychosis
  • paranoia

* image

Laboratory

• complete blood count
  • normochromic normocytic anemia
  • leukopenia
    • neutropenia
    • eosinophilia
    • lymphocytosis
• serum chemistries
  • low serum Na+
  • low serum Cl-
  • low serum HCO3- (metabolic acidosis)
  • high serum K+
  • serum Ca+2: hypercalcemia, generally mild to moderate
  • serum glucose: fasting hypoglycemia
  • serum urea: azotemia
• urinalysis
  • low urinary 17-ketosteroids, high urinary 17-hydroxysteroids
  • low 24 hour urinary free cortisol
• serum cortisol
  • generally low, but generally not useful
  • only 50% of patients with adrenal insufficiency have diagnostic morning serum cortisol of < 3 ug/dL
  • in the presence of severe physiologic stress, serum cortisol < 20 ug/dL suggests adrenal insufficiency
  • random serum cortisol > 20 ug/dL excludes adrenal insufficiency
• serum aldosterone is low (unnecessary if hyponatremia & hyperkalemia)
• serum DHEA-sulfate low
  • due not delay administration of hydrocortisone to obtain serum DHEA sulfate
• plasma ACTH
  • markedly elevated in primary adrenal insufficiency
  • low or inappropriately normal in secondary adrenal insufficiency
• plasma renin activity is high
• cosyntropin (Cortrosyn) stimulation test - test of choice
  • a rise in serum cortisol of > 23 ug/dL rules out adrenal insufficiency
  • not needed if AM serum cortisol is < 3 ug/dL with signs & symptoms of cortisol deficiency
• insulin tolerance test
  • gold standard for evaluation of hypothalamic-pituitary-adrenal axis
  • hazardous test
• steroid 21-hydroxylase antibody in serum (+ in autoimmune adrenalitis)
• PPD -> if tuberculosis is a possible etiology

Radiology

• calcification of adrenals is rarely observed
• computed tomography (CT) of adrenal glands
  • indicated if serum ACTH is elevated
  • autoimmune adrenalitis leads to small adrenal glands
  • infection, hemorrhage & other causes lead to large adrenal glands
• MRI of the brain (sella turcica) if serum ACTH is low or normal

Complications

• ~50% of patients with autoimmune adrenalitis have other endocrine autoimmune diseases (autoimmune polyglandular syndrome)
  • testing indicated

Differential diagnosis

• secondary adrenal failure
  • milder, pigmentation absent
• acanthosis nigricans
  • hyperpigmentation most commonly in intertriginous regions, especially axillae & groin, also neck, knuckles, umbilicus, corners of mouth

Management

• general: glucocorticoid + mineralocorticoid deficiency
  • prednisone 5 mg PO QD + fluodrocortisone 0.05 mg PO QD
• glucocorticoid deficiency
  • hydrocortisone (12-15 mg/m2 daily)
    • 20 mg PO qAM, 10 mg qPM
    • 10 mg TID
    • 12.5-25 mg/day divided BID-TID
    • physiologic replacement of cortisol is 20 mg QD
  • prednisone 2.5-5 mg PO QD
  • for minor illness, stress, minor surgery, fever > 100 F, influenza
    • 2-10 times the oral maintenance dose of to avoid adrenal crisis
    • for dental extraction, twice usual dose of glucocorticoid on the day of surgery & for 1-2 days after
    • dosage increase of glucocorticoid crucial even with minor illness
  • for severe illness, major surgery or injury
    • hydrocortisone 100-150 mg/day IV divided every 6 hours
    • hydrocortisone 100 mg IV, then 50 mg every 6 hours, rapid taper
    • septic shock: 150-200 mg/day
    • dexamethasone 6-8 mg IV QD divided BID/TID (alternative)
  • do not use dexamethasone for chronic glucocorticoid replacement therapy
• mineralocorticoid deficiency
  • fludrocortisone (Florinef) 0.05-0.1 mg PO qAM
    • primary adrenal insufficiency
    • not required if hydrocortisone dose is > 50 mg/day
    • higher doses may be needed if prednisone is used
    • titrate to normal serum sodium, serum potassium & to acceptable blood pressure
  • liberalized salt intake
• DHEA 25-50 mg QD
  • women with mood disorder or low libido
• patient education
  • Medic alert bracelet
  • patients should have & be instructed on use of parenteral glucocorticoids in case of emergency
• follow-up
  • glucocorticoid replacement
    • appetite, well-being, body weight are the best indicators to follow
    • serum ACTH, cortisol & electrolytes do not reflect clinical status & do not need to be monitored
    • signs of Cushing's syndrome suggest over-replacement
    • bone mineral density measurements should be performed periodically
  • mineralocorticoid replacement
    • plasma renin activity is the best indicator of plasma volume & should be titrated to the upper normal range
    • serum K+ levels should be monitored
    • blood pressure should be checked frequently
      • recumbent hypertension is a problem in patients taking fludrocortisone

More general terms

• adrenal insufficiency

More specific terms

• hypoadrenal (Addisonian) crisis; acute adrenal insufficiency
• X-linked adrenal hypoplasia congenital

Additional terms

• 17 hydroxycorticosteroid
• 17 ketosteroid
• aldosterone (Electrocortin, Aldocortin)
• congenital adrenal hypoplasia
• cortisol; hydrocortisone (Cortef, Solu-Cortef, Alphaderm, Cetacort, Cortenema, Nutracort)
• cosyntropin (ACTH, Cortrosyn) stimulation test (delta cortisol test)
• hypoglycemia
• insulin tolerance test (ITT)
• potassium (K+) in serum/plasma
• renin; angiotensinogenase (REN)

Component of

• Schmidt's syndrome; autoimmune polyglandular syndrome type 2

Patient information

Addison's disease patient information