Adrenal insufficiency

Adrenal insufficiency is the decreased production of adrenocortical hormones (glucocorticoids, mineralocorticoids, and adrenal androgens) and can be primary, secondary, or tertiary. Primary adrenal insufficiency (Addison disease) is caused by a disorder of the adrenal glands. The most frequent cause of primary adrenal insufficiency in the US 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) and tertiary adrenal insufficiency is the result of decreased production of CRH (corticotropin-releasing hormone) by the hypothalamus. Decreased levels of ACTH or CRH are seen following sudden cessation of a prolonged glucocorticoid therapy or in pituitary/hypothalamic diseases. Patients with long-standing adrenal insufficiency can present with postural hypotension, nausea, vomiting, weight loss, anorexia, lethargy, depression, and/or chronic hyponatremia. Patients can 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 adrenal crisis, which is a severe, acute type of adrenal insufficiency that manifests with shock, fever, impaired consciousness, and severe abdominal pain. 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 impair adrenal function.

• Autoimmune adrenalitis
  • Most common cause in the US (∼ 80–90% of all cases of primary adrenal insufficiency)
  • Associated with other autoimmune endocrinopathies (see autoimmune polyglandular syndromes)
• Infectious adrenalitis
  • Tuberculosis: most common cause worldwide, but rare in the US
  • CMV disease in immunosuppressed states (especially AIDS)
  • Histoplasmosis
• Adrenal hemorrhage ^[1][2]
  • Sepsis: especially, meningococcal sepsis → hemorrhagic necrosis (Waterhouse‑Friderichsen syndrome)
  • Disseminated intravascular coagulation (DIC)
  • Anticoagulation: especially heparin (HIT) ^[3]
  • Venous thromboembolism, especially in antiphospholipid syndrome (APS) ^[4]
  • Adrenal tumor (most commonly pheochromocytoma) → intratumoral bleeding ^[5]
  • (Short-term) steroid usage ^[6]
  • Trauma (mostly blunt trauma, can also occur postoperatively) ^[7]
  • In neonates: birth trauma, difficult labor (e.g., breech delivery, forceps/vacuum delivery, prolonged labor), maternal diabetes ^[8]
• 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)
  • 21β-hydroxylase deficiency (see congenital adrenal hyperplasia)
• Vitamin B₅ deficiency ^[9]

Secondary adrenal insufficiency

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

• Sudden discontinuation of chronic glucocorticoid therapy or stress (e.g., infection, trauma, surgery) during prolonged glucocorticoid therapy
  • Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis
  • Impaired endogenous cortisol production in addition to discontinuation of steroid treatment, decrease in dosage, or increase in requirement (e.g., stress) → acute glucocorticoid deficiency
• Hypopituitarism: ↓ ACTH → ↓ endogenous cortisol

Tertiary adrenal insufficiency

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

• The most common cause is sudden discontinuation of chronic glucocorticoid therapy: prolonged iatrogenic suppression of hypothalamic-pituitary-adrenal axis (↓ endogenous cortisol) and sudden discontinuation of exogenous steroid treatment → acute glucocorticoid deficiency
• Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, hemorrhage, or anorexia): ↓ CRH → ↓ ACTH → ↓ cortisol release

Secondary and tertiary adrenal insufficiency are far more common than primary adrenal insufficiency!

References:^[10][1][11]

For basic information on the adrenal gland and its functions, see hormones of the adrenal cortex.

• Primary adrenal insufficiency (Addison disease)
  • Damage to the adrenal gland → hypoandrogenism (most common in female patients) , hypoaldosteronism, and hypocortisolism → ↑ ACTH ^[12]
    • ACTH is derived from precursor molecule pro-opiomelanocortin (POMC), which is also a precursor for melanocyte-stimulating hormone (MSH).
    • ↑ Production of POMC (in order to ↑ ACTH production) → ↑ melanocyte-stimulating hormone (MSH) and hyperpigmentation of the skin (bronze skin)
• Secondary adrenal insufficiency
  • ↓ ACTH → hypoandrogenism and hypocortisolism
  • Aldosterone synthesis is not affectedd (mineralocorticoid production is controlled by RAAS and angiotensin II, not by ACTH).
• Tertiary adrenal insufficiency
  • ↓ CRH → ↓ ACTH → hypoandrogenism and hypocortisolism
  • Aldosterone synthesis is not affected.

References:^[11]

Hormonal changes	Clinical features	Laboratory findings	Primary adrenal insufficiency	Secondary adrenal insufficiency	Tertiary adrenal insufficiency
Hypoaldosteronism	Hypotension	Hyponatremia Hyperkalemia Normal anion gap metabolic acidosis	✓	Absent	Absent
Hypocortisolism	Weight loss, anorexia Fatigue, lethargy, depression Muscle aches Gastrointestinal complaints (e.g., nausea, vomiting, diarrhea) Sugar/salt cravings (Orthostatic) hypotension	Hypoglycemia Hyponatremia	✓	✓	✓
Hypoandrogenism	Loss of libido Loss of axillary and pubic hair	↓ DHEA-S	✓	✓	✓
Elevated ACTH	Hyperpigmentation of areas that are not normally exposed to sunlight (e.g., palmar creases, mucous membrane of the oral cavity)	↑ MSH	✓	Absent	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!

Primary adrenal insufficiency Pigments the skin. Secondary adrenal insufficiency Spares the skin. Tertiary adrenal insufficiency is due to Treatment (cortisol).

References:^[13]

Diagnosis is based on clinical presentation and confirmed via endocrine evaluation.

Diagnosis of adrenal insufficiency

General laboratory findings

• Serum electrolytes
  • Hyponatremia
  • Hyperkalemia
  • Normal anion gap metabolic acidosis
  • Mild hypercalcemia (in up to one-third of cases)
• Hypoglycemia
• ↑ Serum creatinine and BUN as a result of hypovolemia
• Complete blood count: eosinophilia

Diagnosis of hypocortisolism

• Best initial test
  • Morning serum cortisol levels: < 3 μg/dL (< 80 nmol/L) without exogenous glucocorticoid administration confirms adrenal insufficiency.
  • OR morning serum ACTH levels (often not quickly available)
    • ↑ ACTH in primary adrenal insufficiency
    • ↓ ACTH in secondary/tertiary adrenal insufficiency
• Confirmatory test
  • ACTH stimulation test (cosyntropin test): measurement of serum cortisol before and 30 minutes after administration of exogenous ACTH (e.g., cosyntropin)
    • Physiological response: exogenous ACTH → ↑ cortisol (failure of cortisol to rise > 20 μg/dL after ACTH administration confirms primary adrenal insufficiency)
    • In secondary/tertiary adrenal insufficiency: exogenous ACTH → ↑ cortisol (usually a rise in cortisol > 20 μg/dL)
  • OR metyrapone stimulation test
    • Metyrapone inhibits 11β hydroxylase → impaired conversion of 11-deoxycortisol to cortisol (last step of cortisol synthesis)
    • Measurement of 11-deoxycortisol and cortisol after administration of metyrapone: Adrenal insufficiency is diagnosed if the 11-deoxycortisol level does not exceed 70 ng/mL and the cortisol level is < 5 μg/dL.
      • Physiological response: metyrapone → ↓ cortisol synthesis → ↑ CRH and ↑ ACTH (negative feedback) → ↑ adrenal steroidogenesis → ↑ 11-deoxycortisol and ↑ cortisol
      • In primary adrenal insufficiency: metyrapone → ↓ cortisol synthesis → ↑ in CRH and ↑ ACTH → no increase in adrenal steroid production → ↓ 11-deoxycortisol and ↑ cortisol
      • In secondary/tertiary adrenal insufficiency: metyrapone → ↓ cortisol → ↓ CRH/ACTH→ no increase in adrenal steroidogenesis → ↓ 11-deoxycortisol and ↑ cortisol

Diagnosis of hypoaldosteronism

• ↑ Plasma renin concentration
• ↓ Urine aldosterone levels

Diagnosis of adrenal hypoandrogenism

• ↓ DHEA-S

Identifying the underlying cause of adrenal insufficiency

• Serum ACTH levels
  • ACTH stimulation test: used to distinguish between primary and secondary/tertiary adrenal insufficiency
    • ↑ ACTH → primary adrenal insufficiency
    • ↓ ACTH → secondary or tertiary adrenal insufficiency
  • CRH stimulation test: used to distinguish between secondary and tertiary adrenal insufficiency ^[14]
    • ↓ ACTH → secondary adrenal insufficiency
    • ↑ ACTH → tertiary adrenal insufficiency
• If primary adrenal insufficiency
  • Screen for autoantibodies against 21-hydroxylase and other autoantibodies associated with autoimmune adrenalitis
  • Adrenal imaging (ultrasound, MRI, CT): to detect, e.g., a lesion, mass, infection, or hemorrhage of the adrenal gland
  • If an infectious etiology is suspected: screen for tuberculosis (chest x-ray) and HIV (combination antigen/antibody tests)
• If secondary adrenal insufficiency
  • Rule out iatrogenic cause: history of long-term cortisol intake
  • Head MRI: to detect pituitary destruction or compression (e.g., trauma, lesions, hemorrhage, tumors)
  • Test for other pituitary hormone deficiencies (e.g., TSH, GnRH, prolactin, GH)
• If tertiary adrenal insufficiency
  • Rule out iatrogenic cause: history of long-term cortisol intake
  • Head MRI: to detect hypothalamic destruction or compression (e.g., trauma, lesions, hemorrhage, tumors)
  • Screen for congenital disorders (e.g., DNA-methylation analysis in Prader-Willi syndrome)

References:^{[15][16][17][18]}

Primary adrenal insufficiency

• Requires both glucocorticoid and mineralocorticoid replacement
  • Glucocorticoid replacement
    • Hydrocortisone (15–25 mg): administered in 2–3 doses daily
      • Two-dose regimen: highest dose in the morning; second dose in the afternoon
      • Three-dose regimen: highest dose in the morning; second dose at lunch; third dose in the afternoon ^[19]
    • Increase glucocorticoid dose during stressful situations (e.g., infection, surgery, trauma).
  • Mineralocorticoid replacement
    • Fludrocortisone (0.1 mg): 1 dose/day–3x/week
    • Lower dosage in case of e.g., hypertension ^[20][19]
• Loss of libido can be treated with dehydroepiandrosterone (DHEA).
• Treatment of underlying causes (e.g., antibiotics for TB infection, tumor resection)

Secondary and tertiary adrenal insufficiency

• Only glucocorticoid replacement; is necessary: hydrocortisone (as above)
• Mineralocorticoid production is not ACTH-dependent and therefore unaltered.
• Loss of libido can be treated with dehydroepiandrosterone (DHEA).
• Treatment of underlying causes (e.g., tumor resection)
• In hypopituitarism: substitution of other hormones (e.g., TSH)

Glucocorticoid replacement therapy with hydrocortisone is required in all forms of adrenal insufficiency!

If the dose of glucocorticoids is not increased during periods of stress, the patient may develop an adrenal crisis!
References:^[21]

• Description: Acute, severe glucocorticoid deficiency that requires immediate emergency treatment.
• Causes
  • 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 infarction (e.g., Waterhouse-Friderichsen syndrome)
  • Pituitary apoplexy
• Clinical features
  • Hypotension, shock
  • Impaired consciousness, coma
  • Fever
  • Vomiting, diarrhea
  • Severe abdominal pain (which resembles peritonitis)
  • Hypoglycemia, hyponatremia, hyperkalemia, and metabolic acidosis
• Therapy
  • Administration of high doses of hydrocortisone: 100 mg IV every 8 hours
    • Alternatively: dexamethasone
      • 4 mg IV every 12 hours
      • Does not interfere with testing, as opposed to hydrocortisone ^[22]
  • Fluid resuscitation; with normal saline to treat hypotension; and hyponatremia
  • Correct hypoglycemia with 50% dextrose
  • Intensive care monitoring

In order to avoid the development of secondary and tertiary adrenal insufficiency, prolonged steroid therapy must be tapered slowly and should never be stopped abruptly.

The 5 S’s of adrenal crisis treatment are: Salt: 0.9% saline, Sugar: 50% dextrose, Steroids: 100 mg hydrocortisone IV every 8 hours, Support: normal saline to correct hypotension and electrolyte abnormalities, Search for underlying disorder

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:^[13][21]

• 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)
    • Less common than APS-2 (1:100,000)
    • Autosomal recessive inheritance; no HLA association
    • Caused by a mutation in the autoimmune regulator gene (AIRE)
    • Age of onset: usually in childhood
    • 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
      • Less commonly: hypogonadism, pernicious anemia, alopecia, vitiligo, hepatitis
  • Type 2 (APS-2, Schmidt syndrome): defined by the occurrence of primary adrenal insufficiency with thyroid autoimmune disease and/or type 1 diabetes mellitus ^[23]
    • More common than APS-1 (1:100)
    • Associated with HLA‑DR3 and/or HLA‑DR4 haplotypes
    • Age of onset: usually in adulthood
    • 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
        • Less commonly: celiac disease, pernicious anemia, alopecia areata, vitiligo
• Diagnostics: condition‑specific antibody tests (e.g., TPO antibodies in Hashimoto thyroiditis, antiparietal cell antibodies in pernicious anemia)
• Therapy: depends on the endocrine deficiency
  • Replacement of deficient hormones (e.g., thyroxin, hydrocortisone, insulin)
  • Antifungal therapy in chronic mucocutaneous candidiasis
  • Vitamin B₁₂ supplementation in pernicious anemia; vitamin D in hypoparathyroidism
  • Immunosuppressive therapy for, e.g., hepatitis, nephritis, pneumonitis

References:^[24]