Adrenal insufficiency

Adrenal insufficiency refers to the decreased production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens). Primary adrenal insufficiency (Addison disease) is caused by a disorder of the adrenal glands. The most frequent cause of primary adrenal insufficiency by far is autoimmune adrenalitis, which may occur sporadically or as a manifestation of polyglandular autoimmune syndromes. Secondary adrenal insufficiency is the result of decreased production of ACTH (adrenocorticotropic hormone). Decreased levels of ACTH are seen following prolonged glucocorticoid therapy or in pituitary/hypothalamic diseases. Patients with long-standing adrenal insufficiency may present with postural hypotension, nausea, vomiting, weight loss, anorexia, lethargy, depression, and/or chronic hyponatremia. Female patients also present with loss of libido as a result of hypoandrogenism. Patients with primary adrenal insufficiency also tend to develop hyperpigmentation of the skin, mild hyperkalemia, and metabolic acidosis. Serum cortisol levels that remain low even after the administration of exogenous ACTH (ACTH stimulation test) confirm the diagnosis of adrenal insufficiency. Glucocorticoid replacement therapy with hydrocortisone is required for all forms of adrenal insufficiency. The dose of glucocorticoids should be increased during periods of stress (e.g., surgery, trauma, infections) in order to prevent an adrenal crisis, a severe, acute type of adrenal insufficiency that presents with fever, impaired consciousness, severe abdominal pain, and hypovolemic shock. Adrenal crisis is life-threatening and should be treated immediately with high doses of hydrocortisone and intravenous fluids.

Primary adrenal insufficiency (Addison disease)

Primary adrenal insufficiency is caused by conditions that directly damage the adrenal gland.

• Autoimmune adrenalitis (most common cause; ∼ 80–90% of all cases of primary adrenal insufficiency)
  • Autoimmune adrenalitis; is usually associated with other autoimmune endocrinopathies (see polyglandular autoimmune syndrome)
• Infections
  • Tuberculosis (2^nd most common cause)
  • CMV disease in immunosuppressed states (especially AIDS)
• Adrenal hemorrhage
  • Waterhouse‑Friderichsen syndrome: meningococcal sepsis → hemorrhagic necrosis
• 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., etomidate, ketoconazole)
  • 21β-hydroxylase deficiency (see congenital adrenal hyperplasia)

Secondary adrenal insufficiency

Secondary adrenal insufficiency is caused by conditions that decrease ACTH production (impaired hypothalamic-pituitary-adrenal axis).

• Sudden discontinuation of glucocorticoids or stress (e.g., infection, trauma, surgery) after prolonged glucocorticoid therapy
  • Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis eventually shuts down the production and release of CRH, ACTH and, in turn, of cortisol.
  • With endogenous production impaired, a sudden discontinuation of steroid treatment, decrease in dosage, or increase in requirement (e.g., stress) will cause a glucocorticoid deficiency.
• Hypopituitarism

Secondary adrenal insufficiency is far more common than primary adrenal insufficiency!

References:^[1][2][3]

• Primary adrenal insufficiency (Addison disease)
  • Damage to the adrenal gland → hypoandrogenism (among female patients only), hypoaldosteronism, and hypocortisolism → ↑ ACTH; ;
• Secondary adrenal insufficiency
  • ↓ ACTH → hypoandrogenism (among female patients only) and hypocortisolism

References:^[3]

Hormone insufficiency	Clinical and/or biochemical features		Primary adrenal insufficiency	Secondary adrenal insufficiency
Hypoaldosteronism	Hypotension	Hyponatremia Hyperkalemia Normal anion gap metabolic acidosis	✓	Absent
Hypocortisolism	Weight loss, anorexia, lethargy, and/or depression Intestinal complaints (nausea, vomiting, and/or diarrhea) Hypotension	Hypoglycemia Hyponatremia	✓	✓
Hypoandrogenism (among female patients only)	Loss of libido Loss of axillary and pubic hair		✓	✓
Elevated ACTH	Hyperpigmentation of areas that are not normally exposed to sunlight (e.g., palmar creases, mucous membrane of the oral cavity)		✓	Absent

Most cases of adrenal insufficiency are subclinical and only become apparent during periods of stress (e.g., surgery, trauma, infections), when the cortisol requirement is higher!
References:^[4]

Diagnosis of adrenal insufficiency

• Diagnosis of hypocortisolism
  • Low serum cortisol levels
  • Confirmatory test: ACTH stimulation test (cosyntropin test)
    • Measurement of serum cortisol before and 30 minutes after administration of exogenous ACTH (e.g., cosyntropin)
    • Serum cortisol levels remain low even after administration of 250 μg of exogenous cosyntropin.
• Diagnosis of hypoaldosteronism
  • ↑ Plasma renin concentration
  • ↓ Urine aldosterone levels
• Diagnosis of adrenal hypoandrogenism
  • ↓ DHEA-S
• Additional laboratory findings
  • Hyponatremia
  • Hyperkalemia and a normal anion gap metabolic acidosis
  • Mild hypercalcemia (in up to ⅓ of cases)
  • Increased serum creatinine and BUN as a result of hypovolemia
  • Eosinophilia
• Metyrapone stimulation test
  • Metyrapone inhibits 11-ß hydroxylase → impaired conversion of 11-deoxycortisol to cortisol (last step of cortisol synthesis)
    • Normal response: ↓ cortisol → ↑ in CRH and ACTH → ↑ adrenal steroidogenesis
    • In primary adrenal insufficiency: ↓ cortisol → ↑ in CRH and ↑ ACTH → no increase in adrenal steroid production
    • In secondary or tertiary adrenal insufficiency: ↓ cortisol → no increase in CRH/ACTH → no increase in adrenal steroidogenesis
  • Rarely performed in the US in favor of serum ACTH assays

Identifying the underlying cause of adrenal insufficiency

• Serum ACTH levels: used to distinguish primary from secondary adrenal insufficiency
  • ↑ ACTH → primary adrenal insufficiency
  • ↓ ACTH → secondary adrenal insufficiency
• If primary adrenal insufficiency
  • Screen for adrenal antibodies and other autoimmune diseases (e.g., Hashimoto thyroiditis, pernicious anemia, type 1 DM)
  • Adrenal imaging (ultrasound, MRI, CT)
  • If an infectious etiology is suspected: chest x-ray, HIV test
• If secondary adrenal insufficiency
  • Rule out iatrogenic Cushing syndrome
  • CNS imaging to detect pituitary tumors
• References:^[5][6]

• Glucocorticoid replacement therapy with hydrocortisone is required in all forms of adrenal insufficiency.
  • In order to emulate the natural diurnal rhythm, the daily dose of hydrocortisone (10–25 mg) is administered in 2–3 doses (e.g., ½–¼–¼).
  • Adjustment of glucocorticoid dosage under stress (infections, surgery, etc.)
• Patients with primary adrenal insufficiency (Addison disease) may require fludrocortisone; in addition to glucocorticoid replacement therapy.
• Loss of libido in female patients can be treated with dehydroepiandrosterone (DHEA).

If the dose of glucocorticoids is not increased during periods of stress (e.g., surgery, febrile infections, trauma), the patient may develop an adrenal crisis!
References:^[7]

• Description: Acute, severe glucocorticoid deficiency that is usually precipitated by one of the following triggers:
  • Stress (e.g., infection, trauma, surgery) in a patient with underlying adrenal insufficiency
  • Sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy
  • Bilateral adrenal hemorrhage or bilateral adrenal infarction (e.g., Waterhouse-Friderichsen syndrome)
  • Pituitary apoplexy
• Clinical features
  • Fever
  • Vomiting, diarrhea
  • Severe abdominal pain (which mimics peritonitis)
  • Impaired consciousness
  • Hypotension and/or shock
  • Hypoglycemia, hyponatremia, hyperkalemia, and metabolic acidosis
• Therapy
  • Administration of high doses of hydrocortisone: 100 mg intravenous hydrocortisone followed by 100–200 mg hydrocortisone over 24 hours
  • Fluid replacement; with normal saline to treat hypotension; and hyponatremia
  • Correct hypoglycemia, hyperkalemia, and metabolic acidosis.
  • Intensive care monitoring

Adrenal crisis can be life-threatening. Therefore, treatment with high doses of hydrocortisone should be started immediately without waiting for diagnostic confirmation of hypocortisolism!
References:^[4][7]

• Definition: Autoimmune polyendocrine syndromes are conditions characterized by multiple endocrine deficiencies as a result of autoimmune disease.
• Types
  • Type 1 (Whitaker syndrome; juvenile form)
    • Autosomal recessive inheritance
    • Age of onset: 3–5 years or during early adolescence
    • Clinical features (one or more of the following features are present)
      • Primary adrenal insufficiency
      • Hypoparathyroidism
      • Hypogonadism
      • Mucocutaneous candidiasis
  • Type 2 (Schmidt syndrome; adult form)
    • Associated with HLA‑DR3 and/or HLA‑DR4 haplotypes
    • Age of onset: 20–60 years
    • Clinical features (one or more of the following features are present)
      • Primary adrenal insufficiency
      • Hashimoto thyroiditis
      • Type 1 diabetes mellitus
      • Pernicious anemia
      • Alopecia
• Diagnostics: condition‑specific antibody tests (e.g., thyroid peroxidase antibodies, parietal cell antibodies)
• Therapy: hormone replacement therapy

Adrenal insufficiency is the most common endocrinopathy in patients with polyglandular autoimmune syndrome (present in over 50% of cases)!