Adrenal insufficiency

Epidemiology

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Etiology

Primary adrenal insufficiency (Addison disease)

• Destruction of the adrenal cortex leading to ↓ cortisol AND ↓ aldosterone.
• Most common cause in developed countries: Autoimmune adrenalitis.
• Other causes: Infections (TB, HIV, fungal), bilateral adrenal hemorrhage (Waterhouse-Friderichsen syndrome in meningococcemia), metastasis.

Secondary & tertiary adrenal insufficiency

• Secondary: Decreased ACTH secretion from the pituitary (e.g., pituitary tumors, Sheehan syndrome).
• Tertiary: Decreased CRH from the hypothalamus. Most common cause: Chronic exogenous steroid use followed by abrupt cessation.
• Leads to ↓ cortisol ONLY. Aldosterone is preserved because it is primarily regulated by the Renin-Angiotensin-Aldosterone System (RAAS), not ACTH.

Feature	Primary AI	Secondary/Tertiary AI
Defect	Adrenal Gland Failure	↓ ACTH / CRH (Pituitary/Hypothalamus)
ACTH	↑ High	↓ Low
Aldosterone	↓ Low	Normal (RAAS intact)
Key Signs	Hyperpigmentation & Hyperkalemia	NO hyperpigmentation or hyperkalemia
Treatment	Cortisol + Fludrocortisone	Cortisol ONLY

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Pathophysiology

Primary adrenal insufficiency (Addison disease)

Damage to the adrenal gland leads to the deficiency in all three hormones produced by the adrenal cortex: androgen, cortisol, and aldosterone.

• Hypoandrogenism
  • Loss of libido
  • Impaired spermatogenesis (in men)
• Hypocortisolism leads to:
  • ↑ ACTH → ↑ production of POMC (in order to increase ACTH production) → ↑ melanocyte-stimulating hormone (MSH) → hyperpigmentation of the skin (bronze skin)
  • ↑ ADH level → retention of free water → dilutional hyponatremia
  • ↓ Expression of enzymes involved in gluconeogenesis → ↓ rate of gluconeogenesis → hypoglycemia
  • Lack of potentiation of catecholamines action → hypotension
• Hypoaldosteronism → hypotension (hypotonic hyponatremia and volume contraction), hyperkalemia, metabolic acidosis

Clinical features

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• Shared Features (due to ↓ Cortisol):
  • Constitutional: Fatigue, weakness, weight loss, anorexia.
  • GI: Nausea, vomiting, abdominal pain, diarrhea.
  • Orthostatic hypotension and dizziness.
  • Hypoglycemia, especially in children.
    • Permissive action
    • Reverse of 诱发三高和溃疡
• Features specific to Primary AI (due to ↓ Aldosterone & ↑ ACTH):
  • Hyperpigmentation: Caused by ↑ ACTH which also stimulates melanocytes (MSH). Visible on skin creases, scars, buccal mucosa.
  • Salt craving.
  • Hyperkalemia and hyponatremia (due to aldosterone deficiency).
  • More severe hypotension/volume depletion.

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Diagnostics

• Initial Labs:
  • Hyponatremia and hyperkalemia (hallmarks of primary disease due to low aldosterone).
  • Hypoglycemia.
  • Eosinophilia may also be present.
    • Glucocorticoids are potent anti-inflammatory agents. One of their key immune-modulating effects is to suppress eosinophils.
  • Morning cortisol level: A low level is suggestive of adrenal insufficiency.
• Confirmatory Test:
  • The ACTH stimulation test (Cosyntropin test) is the gold standard for diagnosis.
  • A baseline cortisol level is drawn, followed by an IV administration of synthetic ACTH (cosyntropin). Cortisol levels are measured again at 30 and 60 minutes.
  • Normal response: A significant rise in cortisol levels (e.g., to >18-20 mcg/dL).
  • Adrenal insufficiency: An insufficient or absent rise in cortisol levels.
• Differentiating Primary vs. Secondary:
  • Plasma ACTH level:
    • High in primary adrenal insufficiency (due to loss of negative feedback).
    • Low or inappropriately normal in secondary/tertiary adrenal insufficiency.
  • Overnight metyrapone stimulation test
    • Physiological response: metyrapone inhibits 11β hydroxylase → impaired conversion of 11-deoxycortisol to cortisol (last step of cortisol synthesis) → ↓ serum cortisol → ↑ in CRH and plasma ACTH (negative feedback) → ↑ in adrenal steroidogenesis → ↑ in 11-deoxycortisol level
    • In primary adrenal insufficiency: metyrapone → ↓ cortisol synthesis → ↑ in CRH/ACTH → no increase in adrenal steroid production → no increase in 11-deoxycortisol or cortisol levels
    • In secondary/tertiary adrenal insufficiency: metyrapone → ↓ cortisol → no increase in CRH/ACTH → no increase in adrenal steroid production → no increase in 11-deoxycortisol or cortisol levels

Treatment

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Steroid replacement

• Glucocorticoids
  • Hydrocortisone
  • Cortisone acetate
  • Prednisolone
• Mineralocorticoids
  • Agent: fludrocortisone (a synthetic mineralocorticoid with mostly mineralocorticoid and limited glucocorticoid effects)

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Adrenal crisis

Adrenal crisis is an acute, severe glucocorticoid deficiency that requires immediate emergency treatment.

Precipitating factors for adrenal crisis

• Stress in patients with underlying adrenal insufficiency e.g.:
  • Gastrointestinal illness (most common)
  • Other infections
  • Perioperative period
• Sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy
• Bilateral adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome)
• Pituitary apoplexy

Tip

In order to prevent the development of secondary and tertiary adrenal insufficiency, prolonged steroid therapy should be tapered slowly rather than stopped abruptly.

Signs and symptoms

• Hypotension, shock
• Impaired consciousness, coma
• Fever
• Vomiting, diarrhea
• Severe abdominal pain (which can resemble peritonitis)

Autoimmune polyglandular syndromes

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• Definition: a set of conditions characterized by autoimmune disease that causes multiple endocrine deficiencies, which affect the hormone-producing (endocrine) glands
• Types
  • Type 1: (APS-1, Whitaker syndrome, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED)
    • Caused by a mutation in the autoimmune regulator gene (AIRE)
      • Facilitates the elimination of self-reactive T cells.
    • Associated endocrine deficiencies (two or more of the following should be present)
      • Most commonly
        • Primary adrenal insufficiency
        • Hypoparathyroidism
        • Chronic mucocutaneous candidiasis
        • Ectodermal dystrophy of skin, nails, and dental enamel
  • Type 2 (APS-2, Schmidt syndrome): defined by the occurrence of primary adrenal insufficiency with thyroid autoimmune disease and/or type 1 diabetes mellitus
    • Main manifestation: primary adrenal insufficiency
      • Associated endocrine deficiencies (one or more of the following may be present)
        • Most commonly
          • Thyroid autoimmune disease (e.g., Hashimoto thyroiditis)
          • Type 1 diabetes mellitus