What does a plasma ACTH level < 1.5 µg/L indicate and how should central adrenal insufficiency be evaluated and managed?

Central Adrenal Insufficiency Evaluation

A plasma ACTH level < 1.5 pg/mL in the context of low cortisol indicates ACTH-independent (adrenal) Cushing's syndrome if cortisol is elevated, or primary adrenal insufficiency if cortisol is low—but this extremely low ACTH value most commonly points to suppressed ACTH from exogenous glucocorticoid use or adrenal autonomy. 1

Understanding ACTH < 1.5 pg/mL

Low or undetectable ACTH levels indicate ACTH-independent pathology, meaning the adrenal glands are either producing excess cortisol autonomously (suppressing pituitary ACTH) or the problem lies at the adrenal level itself. 1

Key Diagnostic Distinctions

• ACTH < 5 pg/mL with elevated cortisol indicates ACTH-independent Cushing's syndrome from an adrenal source (adenoma, carcinoma, or bilateral hyperplasia), requiring adrenal CT or MRI imaging to identify the lesion. 1

• ACTH < 5 pg/mL with low cortisol suggests either primary adrenal insufficiency (though ACTH would typically be markedly elevated >300 pg/mL in true primary AI) or, more commonly, iatrogenic secondary adrenal insufficiency from exogenous steroid suppression. 2, 3

• Any detectable ACTH > 5 pg/mL suggests ACTH-dependent disease, making values < 1.5 pg/mL definitively in the ACTH-independent category. 1

Immediate Clinical Assessment

Rule Out Exogenous Steroid Exposure First

Before pursuing extensive workup, confirm the patient is not taking any form of glucocorticoids—including oral prednisone, inhaled fluticasone, topical steroids, or recent dexamethasone—as these suppress the HPA axis and cause iatrogenic low ACTH. 2, 4

• Exogenous steroids (prednisone ≥20 mg/day for ≥3 weeks, or equivalent doses of other glucocorticoids) reliably suppress ACTH to undetectable levels and cause secondary adrenal insufficiency. 2

• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic because assays measure both endogenous cortisol and therapeutic steroids with variable cross-reactivity. 2

• If the patient is on steroids, diagnostic testing should not be attempted until treatment is discontinued with adequate washout time (hydrocortisone 24 hours, prednisone/prednisolone 48-72 hours, dexamethasone 72-96 hours). 2

Measure Morning Cortisol Simultaneously

• Morning (08:00-09:00h) serum cortisol < 250 nmol/L (< 9 µg/dL) with ACTH < 1.5 pg/mL is highly unusual and suggests either severe adrenal suppression from exogenous steroids or a rare case of combined pituitary and adrenal pathology. 2, 3

• Morning cortisol 140-275 nmol/L (5-10 µg/dL) with low ACTH indicates secondary adrenal insufficiency, typically from pituitary or hypothalamic disease. 2

• Morning cortisol > 550 nmol/L (> 18-20 µg/dL) effectively rules out adrenal insufficiency regardless of ACTH level. 2, 5

Diagnostic Algorithm Based on Cortisol Level

If Cortisol is Elevated (Hypercortisolism with Low ACTH)

This pattern indicates ACTH-independent Cushing's syndrome from an adrenal source. 1

1. Obtain adrenal CT or MRI immediately to identify adrenal adenoma, carcinoma, or bilateral hyperplasia. 1

2. Treatment depends on imaging findings: 1

   • Adrenal adenoma: laparoscopic adrenalectomy
   • Adrenal carcinoma: open adrenalectomy with possible adjuvant therapy
   • Bilateral hyperplasia: medical management or unilateral adrenalectomy

3. Post-dexamethasone suppression cortisol > 50 nmol/L (> 1.8 µg/dL) confirms autonomous cortisol production. 5

If Cortisol is Low (Adrenal Insufficiency with Low ACTH)

This pattern suggests secondary (central) adrenal insufficiency from pituitary or hypothalamic dysfunction, NOT primary adrenal failure. 2, 3

Confirm Diagnosis with ACTH Stimulation Test

Perform the standard 0.25 mg (250 µg) cosyntropin stimulation test to confirm adrenal insufficiency: 2

• Administer 0.25 mg cosyntropin IV or IM
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes
• Peak cortisol < 500 nmol/L (< 18 µg/dL) confirms adrenal insufficiency 2, 6
• Peak cortisol > 550 nmol/L (> 18-20 µg/dL) excludes adrenal insufficiency 2

Note: The low-dose (1 µg) ACTH test is more sensitive for detecting mild secondary adrenal insufficiency but requires bedside dilution and is less practical; the high-dose test is FDA-approved and recommended for routine use. 2, 6

Investigate Pituitary/Hypothalamic Cause

Once secondary adrenal insufficiency is confirmed, evaluate for underlying pituitary or hypothalamic pathology: 7, 3

• Obtain pituitary MRI with gadolinium contrast to assess for pituitary adenoma, apoplexy, empty sella, Sheehan's syndrome, or hypothalamic lesions. 7

• Measure other pituitary hormones (TSH, free T4, LH, FSH, prolactin, IGF-1) to determine if this is isolated ACTH deficiency or part of panhypopituitarism. 3

• CRH stimulation test (100 µg ovine CRH IV bolus) can differentiate pituitary from hypothalamic causes: 7, 8

  • Delayed and prolonged ACTH response suggests hypothalamic dysfunction
  • Absent ACTH response suggests pituitary dysfunction
  • However, this test does not reliably correlate with MRI findings and is not routinely necessary for management

Consider Isolated ACTH Deficiency

Isolated ACTH deficiency is rare but presents with: 3

• Low or undetectable ACTH with low cortisol
• Normal secretion of all other pituitary hormones
• No structural pituitary defects on MRI
• May be autoimmune (lymphocytic hypophysitis) or post-traumatic in adults
• Genetic causes in neonatal/childhood cases

Emergency Management

If the patient presents with unexplained hypotension, collapse, severe vomiting, altered mental status, or other signs of adrenal crisis, treatment must NEVER be delayed for diagnostic testing: 2, 5

1. Immediately administer 100 mg IV hydrocortisone bolus 2
2. Infuse 0.9% saline at 1 L/hour (at least 2L total) 2
3. Draw blood for cortisol and ACTH before steroid administration if feasible, but do not delay treatment 2

Alternative: If diagnosis is uncertain and you still need to perform ACTH stimulation testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 2

Long-Term Management of Confirmed Secondary Adrenal Insufficiency

Glucocorticoid Replacement

All patients with confirmed secondary adrenal insufficiency require lifelong glucocorticoid replacement therapy: 2

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 07:00,5 mg at 12:00,2.5-5 mg at 16:00) to mimic physiological cortisol rhythm 2
• Alternative: cortisone acetate 25-37.5 mg daily or prednisone 3-5 mg daily 2
• Mineralocorticoid replacement (fludrocortisone) is NOT required in secondary AI because the renin-angiotensin-aldosterone system remains intact 2, 3

Stress Dosing Education

Patients must be educated to double or triple their usual dose during illness, fever, or physical stress: 2

• Minor stress: double usual daily dose for 1-2 days
• Moderate stress: hydrocortisone 50-75 mg daily
• Major stress/surgery: hydrocortisone 100-150 mg daily

Safety Measures

• Prescribe emergency injectable hydrocortisone 100 mg IM kit with self-injection training 2
• Mandatory medical alert bracelet or necklace indicating adrenal insufficiency 2
• Carry steroid emergency card at all times 2

Drug Interactions

Adjust hydrocortisone dose for medications that alter cortisol metabolism: 2

• CYP3A4 inducers increase requirements: phenytoin, carbamazepine, rifampin, barbiturates
• CYP3A4 inhibitors decrease requirements: grapefruit juice, licorice

Monitoring

• Annual review with assessment of health, well-being, weight, blood pressure, and serum electrolytes 2
• Screen periodically for new autoimmune disorders (thyroid, diabetes, celiac disease) 2
• Monitor bone mineral density every 3-5 years to assess for glucocorticoid-related complications 2

Critical Pitfalls to Avoid

• Never rely solely on electrolyte abnormalities for diagnosis—hyponatremia may be mild and hyperkalemia is present in only ~50% of primary AI cases (and typically absent in secondary AI). 2

• Do not attempt diagnostic testing in patients actively taking corticosteroids—wait until adequate washout period has elapsed. 2

• Never discontinue hydrocortisone in patients with confirmed non-iatrogenic adrenal insufficiency—these conditions are permanent and stopping replacement precipitates life-threatening adrenal crisis. 2

• When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 2