Epidemiology

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Etiology

Primary adrenal insufficiency (Addison disease)

• Autoimmune adrenalitis
  • Most common cause in the US (∼ 80–90% of all cases of primary adrenal insufficiency)
  • Caused by autoimmune destruction of both adrenal cortices
  • Associated with other autoimmune endocrinopathies
• Infectious adrenalitis
  • Tuberculosis: most common cause worldwide, but rare in the US
  • CMV disease in immunosuppressed states (especially AIDS)
  • Histoplasmosis
• Adrenal hemorrhage
  • Sepsis: especially meningococcal sepsis (endotoxic shock) → hemorrhagic necrosis (Waterhouse-Friderichsen syndrome)
  • Disseminated intravascular coagulation (DIC)
• Infiltration of the adrenal glands
  • Tumors (adrenocortical tumors, lymphomas, metastatic carcinoma)
  • Amyloidosis
  • Hemochromatosis
• Adrenalectomy
• Impaired activity of enzymes that are responsible for cortisol synthesis
  • Cortisol synthesis inhibitors (e.g., rifampin, fluconazole, phenytoin, ketoconazole): drug-induced adrenal insufficiency
  • 21β-hydroxylase deficiency

Tertiary adrenal insufficiency

Tertiary adrenal insufficiency is caused by conditions that decrease CRH production.

• The most common cause is sudden discontinuation of chronic glucocorticoid therapy.
• Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, hemorrhage, or anorexia): ↓ CRH → ↓ ACTH → ↓ cortisol release

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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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Hypocortisolism

• Weight loss, anorexia
• Fatigue, lethargy, depression
• Muscle aches
• Weakness
• Gastrointestinal complaints (e.g., nausea, vomiting, diarrhea)
• Permissive action
  • Sugar cravings
  • (Orthostatic) hypotension
    • Glucocorticoids play an important role in catecholamine‑induced vasoconstriction and myocardial contractility.
    • Think about 诱发三高和溃疡

Lab findings

• Hypoglycemia
  • Glucocorticoids inhibit peripheral glucose utilization and increase gluconeogenesis.
• Hyponatremia
  • Glucocorticoids inhibit ADH secretion and thereby prevent excessive water retention. With adrenal insufficiency, ADH secretion is disinhibited causing increased reabsorption of free water with subsequent dilution hyponatremia.

Hypoaldosteronism

• Hypotension
• Salt craving

Lab findings

• Hyponatremia
• Hyperkalemia
• Normal anion gap metabolic acidosis

Hypoandrogenism

• Loss of libido
• Loss of axillary and pubic hair

Lab findings

• ↓ DHEA-S

Elevated ACTH

• Hyperpigmentation of areas that are not normally exposed to sunlight (e.g., palmar creases, mucous membrane of the oral cavity) → tanned skin
  • caused by increased production of MSH (Melanocyte-Stimulating Hormone), which is cleaved from the same precursor peptide (POMC, Pro-opiomelanocortin) as ACTH.

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Diagnostics

• 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