Addison’s Disease

ACUTE ADRENAL FAILURE—ADRENAL CRISIS

Definition and Importance

• Acute adrenal failure (adrenal crisis) is an endocrine emergency, potentially fatal if untreated.
• Dominant features: Dehydration and cardiovascular collapse (shock).

Clinical Settings for Adrenal Crisis

1. Known Primary Adrenal Insufficiency
   • Omission of glucocorticoid therapy.
   • Inadequate dose increase during physical stress (e.g., infection, surgery).
2. Undiagnosed Primary Adrenal Insufficiency
   • Undergoing major stress without prior recognition (acute infection, trauma, etc.).
3. Necrosis of Adrenals
   • Intra-adrenal hemorrhage/infarction.
   • May be caused by infection, trauma, anticoagulant therapy, or coagulopathy.
4. Secondary Adrenal Insufficiency (less common cause)
   • Intact mineralocorticoid secretion usually prevents crisis, but severe stress or abrupt withdrawal of high-dose exogenous glucocorticoids can precipitate.

Adrenal Hemorrhage

• Consider in shock with infection, trauma, anticoagulation (heparin/warfarin), or coagulopathy (e.g., antiphospholipid syndrome).
• Possible back/flank/abdominal pain from intra-adrenal bleeding.
• Fulminant Meningococcemia: Hemorrhagic destruction of both adrenals → Waterhouse-Friderichsen syndrome (especially children/young adults).
  • Presents with purpura, meningitis, shock, DIC, purpura fulminans.

Clinical Presentation

• Shock: Dehydration, hypotension (circulatory collapse).
• Additional Symptoms: Anorexia, nausea, vomiting, abdominal pain, fever, confusion, lethargy.
• Possible Preexisting Adrenal Failure signs: Hyperpigmentation, weight loss, hyponatremia, hyperkalemia.
• Misdiagnosis Risk: Fever + abdominal pain can mimic an acute surgical abdomen → potentially disastrous unnecessary surgery.

Empiric Treatment

• Consider in severely ill patients with shock refractory to fluids and pressors.
• Do not delay therapy for diagnostic test results if adrenal crisis is suspected.

Treatment for Adrenal Crisis

1. Glucocorticoid Replacement
   • Hydrocortisone sodium succinate: 100 mg IV bolus initially.
   • Continue 100 mg IV q6–8h until resolution of precipitating illness, then taper.
2. Volume Repletion
   • Dextrose in isotonic saline (2–4 L over 4 hours), adjusted for comorbidities and response.
3. Identify Underlying Cause
   • Search for infection, hemorrhage, infarction, or other triggers.
4. Monitoring
   • Frequent checks of serum electrolytes, acid–base status, glucose, renal function.

CHRONIC ADRENAL INSUFFICIENCY

Rate and Extent of Adrenal Destruction

• >90% cortical destruction needed for overt clinical insufficiency.
• Slow Progression: May remain subclinical until precipitated by stress (infection, trauma, surgery).

Signs and Symptoms

• Both Glucocorticoid & Mineralocorticoid Deficiency (Primary Failure):
  • Fatigue, generalized weakness, diffuse myalgias, arthralgias.
  • Anorexia, weight loss, nausea, vomiting, abdominal pain.
  • Psychiatric changes (irritability, depression, apathy).
  • Postural hypotension, hyperpigmentation, salt craving.
  • Hyponatremia, hyperkalemia, mild normocytic anemia.
  • Hypoglycemia (more common in children).
• Hyperpigmentation:
  • Increased ACTH → MSH effect.
  • Darkening of friction areas (knees, knuckles, elbows), belt line, scars, inner lip surfaces, palmar creases, areola, freckles.
  • Vitiligo (~20% of autoimmune Addison’s) from autoimmune destruction of melanocytes.

Gender-Specific

• Women: Loss of axillary & pubic hair, ↓libido due to low adrenal androgens.
• Men: Testicular androgens → minimal androgen deficiency signs.

Etiologies of Primary Adrenal Failure

1. Autoimmune Adrenalitis (~80% in developed countries).
2. Infections (tuberculosis historically; fungal, HIV).
3. Metastatic Cancer (e.g., lung, breast, melanoma).
4. Adrenal Hemorrhage (trauma, antiphospholipid syndrome).
5. Adrenoleukodystrophy.
6. Bilateral Adrenalectomy.
7. Drug-Induced (mitotane, ketoconazole).
8. Congenital (adrenal hypoplasia e.g., DAX1 or SF-1 mutations).

Autoimmune Associations

• 21-Hydroxylase Antibodies: Nearly universal in autoimmune Addison’s.
• Polyglandular Autoimmune Syndrome Type II (APS2):
  • Addison’s + autoimmune thyroid disease + type 1 diabetes mellitus.
  • More common in women, onset 20–40 years old.
• Polyglandular Autoimmune Syndrome Type I (APS1):
  • Rare, autosomal recessive (AIRE gene mutations).
  • Triad: Hypoparathyroidism, chronic mucocutaneous candidiasis, Addison’s.

LABORATORY FINDINGS AND TREATMENT OF PRIMARY ADRENAL INSUFFICIENCY

Lab Findings

• Low Cortisol, High ACTH.
• Hyponatremia, Hyperkalemia (loss of aldosterone).
• Mild metabolic acidosis, azotemia from volume depletion.
• Low DHEA-S, androstenedione → female loss of body hair.
• Cosyntropin Stimulation Test: No significant rise in cortisol.

Treatment Principles

1. Glucocorticoid Replacement
   • Hydrocortisone, cortisone acetate, or prednisone.
   • Stress Dosing for major infections, surgery, trauma (2–3× usual dose).
2. Mineralocorticoid Replacement
   • Fludrocortisone (50–200 µg daily) to normalize serum K⁺, Na⁺, BP.
   • Adjust dose by checking for hypokalemia, edema, or persistent hyperkalemia/hyponatremia.
3. Patient Education
   • Dose adjustments during illness, use of IM injection if vomiting.
   • Medical identification (bracelet/card “adrenal insufficiency—give cortisone”).
   • Keep emergency dexamethasone syringes for self-injection.

Perioperative Management

• Surgery with General Anesthesia: Stress dose coverage (e.g., methylprednisolone 20–40 mg IM pre-op, taper over 2–3 days).
• No Additional Mineralocorticoid typically needed until oral intake resumes.

LABORATORY FINDINGS AND TREATMENT OF SECONDARY ADRENAL INSUFFICIENCY

Key Distinctions from Primary

1. No Hyperpigmentation: ACTH is low/normal (no MSH effect).
2. Aldosterone Levels usually normal (RAAS intact) → minimal hyperkalemia or salt craving.
3. Possible Hyponatremia: due to impaired free-water excretion, elevated vasopressin.
4. May Present with pituitary/hypothalamic mass symptoms or other pituitary hormone deficits (e.g., hypothyroidism, hypogonadism).

Lab Findings

• Low Cortisol, Low/Undetectable ACTH → diagnosing certain if cortisol <5 µg/dL at 8 am with severely low ACTH.
• Cosyntropin Stimulation may show a delayed rise but peak <18 µg/dL.

Treatment

1. Glucocorticoid Replacement
   • No mineralocorticoid needed (aldosterone normal).
   • Hydrocortisone or equivalent, often 2/3 AM, 1/3 PM dosing.
2. Avoid Over- or Undertreatment
   • Monitor clinical signs.
3. Stress Dosing for severe illness or surgery.
4. If Additional Pituitary Deficits: Manage hypothyroidism, hypogonadism, etc. after ensuring adequate cortisol replacement.