Adrenal Insufficiency and Addison Disease

• Adrenal insufficiency (AI) is a life-threatening condition characterized by inadequate production of adrenocortical hormones
• Primary AI (Addison disease): Direct destruction or dysfunction of the adrenal cortex → deficiency of ALL adrenal hormones (cortisol, aldosterone, and androgens)
• Secondary/Central AI: Inadequate ACTH production from pituitary (secondary) or CRH from hypothalamus (tertiary) → isolated cortisol deficiency (aldosterone remains normal)
• Can present as chronic insufficiency or acute crisis (medical emergency)

The adrenal glands, located above the kidneys, produce several essential hormones. The outer layer, the adrenal cortex figure 1, synthesizes 3 classes of hormones:

• Glucocorticoids (primarily cortisol): Maintain vascular tone, glucose homeostasis, and stress response
• Mineralocorticoids (primarily aldosterone): Regulate blood pressure and potassium balance through renal sodium retention and potassium excretion
• Androgens (eg, DHEA): Contribute to sexual function in females (testes are main source in males)

The hypothalamic-pituitary-adrenal (HPA) axis regulates glucocorticoid production figure 2:

• Stress → Hypothalamus releases CRH → Pituitary releases ACTH → Adrenal cortex releases cortisol
• Cortisol exerts negative feedback on both hypothalamus and pituitary
• Aldosterone secretion is regulated by RAAS (not HPA axis) - important distinction!

Primary Adrenal Insufficiency (Addison Disease)

• Autoimmune adrenalitis (80-90% in developed countries) التهاب الغدة الكظرية المناعي
  • Most common cause in resource-rich countries
  • Associated with other autoimmune conditions (polyglandular autoimmune syndrome, hypothyroidism, vitiligo)
  • Anti-21-hydroxylase antibodies present
  • Can be triggered by checkpoint inhibitors (eg, nivolumab)
• Infections
  • Tuberculosis - most common cause worldwide, especially in endemic areas السل
  • Disseminated fungal infections (histoplasmosis)
  • HIV-related (CMV, mycobacteria)
• Adrenal hemorrhage نزيف الغدة الكظرية
  • Waterhouse-Friderichsen syndrome (meningococcemia)
  • Anticoagulation therapy
  • Antiphospholipid syndrome
  • Trauma, severe sepsis
• Others: Metastatic cancer (lung, breast, kidney), adrenoleukodystrophy (X-linked, VLCFAs accumulation)

Secondary/Central Adrenal Insufficiency

• Exogenous glucocorticoid withdrawal (MOST COMMON) إيقاف الكورتيزون الخارجي figure 3
  • Risk with ≥5 mg prednisone daily for ≥2 weeks
  • HPA axis suppression can last months after discontinuation
• Pituitary causes
  • Pituitary tumors, apoplexy
  • Sheehan syndrome (postpartum pituitary necrosis)
  • Lymphocytic hypophysitis
  • Hemochromatosis
• Hypothalamic causes: Craniopharyngioma, radiation, sarcoidosis

Primary AI: Destruction of >90% of adrenal cortex → Loss of all three zones:

• Zona glomerulosa → ↓Aldosterone → Na+ wasting, K+ retention, hypotension
• Zona fasciculata → ↓Cortisol → Hypoglycemia, weakness, ↑ACTH (loss of negative feedback) → Hyperpigmentation
• Zona reticularis → ↓Androgens → Decreased libido, loss of pubic/axillary hair (women only)

Secondary AI: ↓ACTH → ↓Cortisol only (aldosterone production maintained by RAAS)

Chronic Adrenal Insufficiency

Summary of primary versus central/secondary AI is provided in this table table 1.

Acute Adrenal Crisis أزمة قصور الكظر الحادة

• Precipitating factors: Surgery, infection, trauma, stress, endoscopy
• Clinical features:
  • Severe hypotension/shock (refractory to fluids/pressors)
  • Fever, confusion, altered mental status
  • Severe abdominal pain (may mimic acute abdomen)
  • Nausea, vomiting
  • Hypoglycemia

Step-by-Step Approach

1. 8 AM serum cortisol:
   • >15 μg/dL: Rules out AI
   • <5 μg/dL: Confirms AI
   • 5-15 μg/dL: Indeterminate → Do ACTH stimulation test
2. ACTH (Cosyntropin) Stimulation Test اختبار تحفيز ACTH:
   • Give 250 μg cosyntropin IV/IM
   • Measure cortisol at 30 and 60 minutes
   • Normal response: Cortisol >18-20 μg/dL
   • Abnormal: No rise or <18 μg/dL = AI confirmed
3. Differentiate primary vs secondary:
   • Measure baseline ACTH before cosyntropin
   • High ACTH = Primary AI
   • Low/normal ACTH = Secondary AI
4. Evaluate etiology:
   • Primary AI: Check anti-21-hydroxylase antibodies, CT adrenals, consider TB
   • Secondary AI: Review medications, MRI pituitary

Acute Adrenal Crisis (Emergency!)

1. Immediate IV hydrocortisone 100 mg (or dexamethasone 4 mg if diagnosis not confirmed)
2. Aggressive IV fluid resuscitation (0.9% saline)
3. Correct hypoglycemia with D50W
4. Treat precipitating cause (infection, etc.)
5. Taper IV glucocorticoids once stable

Chronic Management

• Primary AI:
  • Hydrocortisone 15-25 mg/day (divided doses: 2/3 morning, 1/3 afternoon)
  • Fludrocortisone 0.05-0.2 mg daily (mineralocorticoid replacement)
  • DHEA for women with low libido
• Secondary AI:
  • Hydrocortisone only (no fludrocortisone needed)
• Important: In patients with both AI and central hypothyroidism, treat AI FIRST before thyroid hormone (can precipitate crisis)

Stress Dose Steroids جرعات الكورتيزون في حالات الإجهاد

Perioperative management details are provided in table 2.