What are the causes of low serum cortisol (hypocortisolism)?

Causes of Low Serum Cortisol (Hypocortisolism)

Low serum cortisol is most commonly caused by primary adrenal insufficiency (autoimmune destruction of adrenal glands), secondary adrenal insufficiency (pituitary disorders), or glucocorticoid-induced adrenal insufficiency (the most common form). 1, 2

Primary Adrenal Insufficiency Causes

• Autoimmune adrenalitis - accounts for over 80% of primary adrenal insufficiency cases 3
• Infections:
  • Tuberculosis
  • Fungal infections
  • HIV-related opportunistic infections
• Infiltrative disorders:
  • Metastatic cancer
  • Amyloidosis
  • Hemochromatosis
• Adrenal hemorrhage or infarction
• Congenital adrenal hyperplasia
• Medications:
  • High-dose azole antifungal therapy
  • Immune checkpoint inhibitors 4
• Surgical removal of adrenal tissue

Secondary Adrenal Insufficiency Causes

• Pituitary tumors
• Pituitary surgery or radiation
• Pituitary hemorrhage or infarction (Sheehan syndrome)
• Inflammatory conditions:
  • Hypophysitis
  • Sarcoidosis
• Infiltrative disorders:
  • Hemochromatosis
  • Langerhans cell histiocytosis
• Medications:
  • Opioids
  • Immune checkpoint inhibitors 4

Tertiary Adrenal Insufficiency Causes

• Hypothalamic disorders
• Isolated CRH deficiency (rare) 5

Glucocorticoid-Induced Adrenal Insufficiency

• Most common form of adrenal insufficiency 2
• Caused by:
  • Oral glucocorticoids (≥5 mg prednisolone equivalent for ≥1 month) 1
  • Injectable glucocorticoids
  • Long-term use of high-potency topical steroids 1
  • Inhaled corticosteroids (high doses)

Laboratory Findings in Different Types of Hypocortisolism

Primary Adrenal Insufficiency

• Low morning cortisol (<5 μg/dL)
• High ACTH levels
• Low DHEAS levels
• Often with electrolyte abnormalities (hyponatremia, hyperkalemia) 1, 2

Secondary/Tertiary Adrenal Insufficiency

• Low or intermediate morning cortisol (5-10 μg/dL)
• Low or low-normal ACTH levels
• Low DHEAS levels
• Typically normal electrolytes 1, 2

Diagnostic Approach

1. Morning cortisol and ACTH measurement (8 AM preferred)

   • Cortisol <3 μg/dL strongly suggests adrenal insufficiency 1
   • Cortisol >15 μg/dL makes it unlikely 1
   • Intermediate values require further testing

2. ACTH stimulation test (250-μg)

   • Peak cortisol <18 μg/dL (500 nmol/L) confirms adrenal insufficiency 1
   • More accurate in primary than secondary adrenal insufficiency

3. Additional testing for specific causes

   • Adrenal antibodies (autoimmune adrenalitis)
   • Adrenal imaging (CT for hemorrhage, metastasis)
   • Pituitary MRI (for secondary causes) 1

Clinical Pearls and Pitfalls

• Symptoms of adrenal insufficiency are often nonspecific (fatigue, weight loss, nausea)
• Hypocortisolism can cause secondary endocrine abnormalities including reversible hypothyroidism, hyperprolactinemia, and hypercalcemia 3
• Patients with comorbidities like asthma and diabetes have higher risk of adrenal crisis 1
• Adrenal crisis is a life-threatening emergency requiring immediate treatment with IV hydrocortisone and fluid resuscitation 1
• Always consider adrenal insufficiency in patients who have recently tapered or discontinued glucocorticoid therapy 2

Early recognition of hypocortisolism is crucial to prevent potentially fatal adrenal crisis, especially during times of physiological stress such as illness, surgery, or trauma.