What are the causes and effects of low cortisol levels (adrenal insufficiency) on the body?

Low Cortisol Levels: Causes and Effects on the Body

Primary Causes of Low Cortisol (Adrenal Insufficiency)

Low cortisol levels result from three main mechanisms: primary adrenal destruction (Addison's disease), pituitary/hypothalamic dysfunction causing secondary adrenal insufficiency, or suppression from exogenous glucocorticoid use—each requiring different diagnostic and treatment approaches. 1

Primary Adrenal Insufficiency (Addison's Disease)

• Autoimmune destruction accounts for approximately 80-85% of cases in Western populations, characterized by high ACTH with low cortisol 1, 2
• Infectious causes including tuberculosis and fungal infections can destroy adrenal tissue 3
• Pharmacological inhibition from high-dose azole antifungal therapy 3
• Congenital adrenal hyperplasia and surgical removal of adrenal cortical tissue 3
• Adrenal hemorrhage, metastatic disease, or infiltrative processes identified through CT imaging when autoantibodies are negative 1

Secondary Adrenal Insufficiency

• Pituitary tumors, hemorrhage, or surgery affecting ACTH production, characterized by low ACTH with low cortisol 1, 3
• Inflammatory or infiltrative conditions such as hypophysitis, sarcoidosis, or hemochromatosis 3
• Radiation therapy to the pituitary region 3
• Medications suppressing ACTH including opioids 3

Glucocorticoid-Induced Adrenal Insufficiency

• Most common form of adrenal insufficiency, occurring after prolonged supraphysiological glucocorticoid administration 3
• Any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks is at risk for HPA axis suppression 1
• Inhaled steroids such as fluticasone can also suppress the HPA axis 1

Clinical Effects on the Body

Metabolic and Energy Effects

• Profound fatigue and weakness occur in 50-95% of patients, representing the most common presenting symptom 3, 2
• Weight loss and anorexia affect 43-73% of patients due to cortisol's role in maintaining appetite and metabolism 3
• Hypoglycemia may occur, particularly in children, due to impaired gluconeogenesis 1, 2

Gastrointestinal Manifestations

• Nausea and vomiting present in 20-62% of patients, often worse in the morning 1, 3
• Abdominal pain with peritoneal irritation can mimic acute surgical conditions 1
• Severe vomiting and/or diarrhea are common precipitating events for adrenal crisis 1

Cardiovascular and Fluid/Electrolyte Effects

• Hypotension and orthostatic hypotension result from both glucocorticoid and mineralocorticoid deficiency in primary AI 1, 4
• Hyponatremia is present in 90% of newly diagnosed cases, caused by vasopressin excess and impaired free water excretion 1, 2
• Hyperkalemia occurs in only approximately 50% of primary AI cases, so its absence does not rule out the diagnosis 1
• Vasopressor-resistant hypotension in critically ill patients may indicate adrenal insufficiency 1

Neurological and Psychiatric Effects

• Confusion, altered mental status, and loss of consciousness can occur in severe cases or adrenal crisis 1
• Enhanced stress sensitivity and inability to cope with physical or emotional stressors 5
• Difficulty concentrating and cognitive impairment 2

Musculoskeletal Effects

• Muscle pain, cramps, and generalized weakness are frequently reported 1
• Chronic pain syndromes may be associated with hypocortisolism 5

Dermatological Manifestations

• Hyperpigmentation is a distinguishing feature of primary adrenal insufficiency due to elevated ACTH stimulating melanocytes 1
• Normal skin color in secondary adrenal insufficiency due to low ACTH 1

Renal Effects

• Increased creatinine from prerenal renal failure due to volume depletion 1
• Mild hypercalcemia occurs in some patients, though the mechanism is unclear 1

Secondary Endocrine Effects

• Glucocorticoid-reversible hypothyroidism can occur with cortisol deficiency 2
• Hyperprolactinemia may develop secondary to cortisol deficiency 2

Life-Threatening Complication: Adrenal Crisis

Adrenal crisis represents a medical emergency with high mortality if untreated, requiring immediate recognition and treatment without delay for diagnostic procedures. 1, 3

Clinical Features of Adrenal Crisis

• Severe hypotension and shock with dehydration 1
• Severe weakness, confusion, and altered mental status progressing to coma 1
• Severe vomiting and/or diarrhea 1
• Unexplained collapse with gastrointestinal symptoms 1

Emergency Management

• Immediate IV hydrocortisone 100 mg bolus plus 0.9% saline infusion at 1 L/hour (at least 2L total) 1, 3
• Never delay treatment for diagnostic procedures if adrenal crisis is suspected 1, 3
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 1

Critical Diagnostic Pitfalls

• Do not rely on electrolyte abnormalities alone—10-20% of patients have normal electrolytes at presentation 1
• Absence of hyperkalemia does not exclude adrenal insufficiency—it occurs in only 50% of cases 1
• Morning cortisol levels are unreliable in patients on exogenous steroids—they will be falsely low due to HPA suppression 1
• Adrenal insufficiency can present identically to SIADH—always perform cosyntropin stimulation test to exclude AI before diagnosing SIADH 1
• Some patients with early primary AI may have normal basal cortisol levels with elevated ACTH—this still indicates adrenal insufficiency 6