Epidemiology

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

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

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.

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

Steroid replacement

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

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

Signs and symptoms

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

Autoimmune polyglandular syndromes

• 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