What is the differential diagnosis and management approach for a patient with suspected secondary adrenal insufficiency?

Differential Diagnosis of Secondary Adrenal Insufficiency

Secondary adrenal insufficiency is characterized by low cortisol with low or inappropriately normal ACTH, and the differential diagnosis must systematically evaluate pituitary, hypothalamic, and iatrogenic causes. 1

Primary Etiologic Categories

Iatrogenic (Most Common)

• Glucocorticoid-induced adrenal insufficiency is the most common cause of secondary adrenal insufficiency in clinical practice, occurring after administration of supraphysiological doses of glucocorticoids that suppress the hypothalamic-pituitary-adrenal (HPA) axis 2
• Any patient taking ≥20 mg/day prednisone or equivalent for ≥3 weeks who develops unexplained hypotension should be presumed to have adrenal insufficiency until proven otherwise 1
• Exogenous steroids including oral prednisolone, inhaled fluticasone, and other corticosteroid formulations can suppress the HPA axis and cause secondary adrenal insufficiency 1
• Medications that suppress corticotropin production include opioids, which are an increasingly recognized cause 2

Pituitary Pathology

• Pituitary tumors (adenomas, craniopharyngiomas) represent the most frequent non-iatrogenic cause of secondary adrenal insufficiency 3
• Pituitary hemorrhage (Sheehan syndrome postpartum, apoplexy) can cause acute ACTH deficiency 2
• Pituitary surgery or radiation therapy can result in delayed-onset isolated ACTH deficiency 2
• Inflammatory or infiltrative conditions including hypophysitis, sarcoidosis, and hemochromatosis can destroy ACTH-producing cells 2

Hypothalamic Disorders

• Hypothalamic tumors or masses compressing the pituitary stalk can disrupt corticotropin-releasing hormone (CRH) secretion 2
• Traumatic brain injury with hypothalamic damage may present with delayed secondary adrenal insufficiency 1
• Infiltrative diseases affecting the hypothalamus (histiocytosis, lymphoma) can impair CRH production 2

Idiopathic Isolated ACTH Deficiency

• Idiopathic delayed-onset isolated secondary adrenal insufficiency without triggering factors is rare but increasingly recognized, presenting with chronic hyponatremia and nonspecific symptoms 4
• This diagnosis requires exclusion of all other causes and normal pituitary imaging 4

Diagnostic Algorithm

Initial Laboratory Evaluation

• Obtain paired early-morning (8 AM) serum cortisol and plasma ACTH as the first-line diagnostic test 1, 2
• Morning cortisol 5-10 µg/dL (140-275 nmol/L) with low or inappropriately normal ACTH is highly suggestive of secondary adrenal insufficiency 1, 2
• Measure DHEA-S levels, which are typically low or low-normal in secondary adrenal insufficiency 2, 4
• Obtain basic metabolic panel: hyponatremia is present in 90% of cases, but hyperkalemia is absent (unlike primary adrenal insufficiency) 1, 2

Confirmatory Testing

• For intermediate morning cortisol values (5-14.5 µg/dL), perform the cosyntropin stimulation test: administer 0.25 mg cosyntropin IV or IM, measure cortisol at 30 and 60 minutes, with peak cortisol <500 nmol/L (<18 µg/dL) diagnostic of adrenal insufficiency 1, 5, 2
• Critical pitfall: The cosyntropin test can give false-normal results in early or partial secondary adrenal insufficiency because the adrenal glands may still respond to supraphysiological ACTH stimulation 1, 6
• If secondary adrenal insufficiency is strongly suspected despite normal cosyntropin test, consider insulin tolerance test (gold standard) or metyrapone test 6, 7

Etiologic Workup

• Order MRI of the sella turcica to evaluate for pituitary masses, hemorrhage, or structural abnormalities 4
• Assess other pituitary hormone axes (TSH, LH/FSH, prolactin, IGF-1) to identify additional pituitary hormone deficiencies that suggest pituitary pathology 1
• Obtain detailed medication history including all corticosteroid exposures (oral, inhaled, topical, intra-articular) and opioid use 1, 2
• Measure renin and aldosterone levels: these should be normal in secondary adrenal insufficiency (unlike primary) since the renin-angiotensin-aldosterone system remains intact 1, 4

Management Approach

Acute/Severe Presentation (Adrenal Crisis)

• Never delay treatment of suspected adrenal crisis for diagnostic procedures—this can be fatal 1, 5, 7
• Immediately administer IV hydrocortisone 100 mg bolus, followed by 100 mg every 6-8 hours 1, 5
• Infuse 0.9% saline at 1 L/hour (at least 2L total) for volume resuscitation 1, 5
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 1
• Alternative: If diagnosis uncertain and you still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1, 5

Chronic Replacement Therapy

• Initiate glucocorticoid replacement with hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM to approximate physiological cortisol secretion) 1, 2
• Alternative regimen: prednisone 3-5 mg daily 2
• Do NOT add fludrocortisone in secondary adrenal insufficiency (only needed in primary adrenal insufficiency) since mineralocorticoid function is preserved 1, 2
• Critical consideration: If treating concurrent hypothyroidism and adrenal insufficiency, always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1

Patient Education (Mandatory)

• All patients must receive education on stress dosing: double or triple dose during illness, fever, or physical stress 1
• Prescribe hydrocortisone 100 mg IM injection kit with self-injection training for emergency use 1
• Patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency to trigger stress-dose corticosteroids by emergency personnel 1, 5
• Educate on warning signs of impending adrenal crisis: severe fatigue, nausea/vomiting, hypotension, confusion 1

Follow-up and Monitoring

• For glucocorticoid-induced adrenal insufficiency, test for HPA axis recovery after 3 months of maintenance therapy or after weaning off corticosteroids 1
• Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods 1
• Mandatory endocrine consultation for newly diagnosed patients, pre-operative planning, and recurrent adrenal crises 1

Common Pitfalls to Avoid

• Do not rely on electrolyte abnormalities alone: hyperkalemia is absent in secondary adrenal insufficiency (unlike primary), and 10-20% of patients may have normal electrolytes 1
• Do not attempt diagnostic testing while patient is on corticosteroids: exogenous steroids suppress the HPA axis and lead to false-positive findings 1, 6
• Do not assume normal cosyntropin test excludes secondary adrenal insufficiency: approximately one-third to one-half of patients on chronic prednisone fail cosyntropin testing despite adequate adrenal reserve 1
• Do not start thyroid replacement before corticosteroids: this can precipitate life-threatening adrenal crisis 1