How to assess for adrenal insufficiency in a patient with suspected primary hypothyroidism, elevated Thyroid-Stimulating Hormone (TSH), low free Triiodothyronine (T3), normal Thyroxine (T4), and positive anti-Thyroid Peroxidase (anti-TPO) antibodies?

Assessment for Adrenal Insufficiency in Suspected Primary Hypothyroidism

In patients with confirmed primary hypothyroidism (elevated TSH, positive anti-TPO antibodies), screen for adrenal insufficiency before initiating or increasing levothyroxine, as starting thyroid hormone replacement can precipitate life-threatening adrenal crisis in patients with concurrent adrenal insufficiency. 1, 2, 3

Critical Screening Indications

Screen for adrenal insufficiency when the following features are present that cannot be fully explained by hypothyroidism alone:

• Unexplained hypotension (systolic BP <100 mmHg or orthostatic drops >20 mmHg systolic) 1
• Hyponatremia (serum sodium <135 mEq/L) 1
• Hyperpigmentation of skin, particularly in sun-exposed areas, palmar creases, or buccal mucosa 1
• Hypoglycemia (glucose <70 mg/dL) without other explanation 1
• Hyperkalaemia (potassium >5.0 mEq/L) 1
• Unexplained weight loss despite hypothyroid symptoms 1
• Salt craving or history of consuming excessive salt 1

Diagnostic Algorithm

Step 1: Paired Morning Cortisol and ACTH Measurement

Obtain fasting 8 AM serum cortisol and plasma ACTH simultaneously (patient must be off any exogenous glucocorticoids for at least 24 hours, though oral prednisolone, dexamethasone, and inhaled fluticasone may confound interpretation): 1, 3

• Serum cortisol <250 nmol/L (9 mcg/dL) with elevated ACTH = diagnostic of primary adrenal insufficiency 1
• Serum cortisol <400 nmol/L (14.5 mcg/dL) with elevated ACTH = strong suspicion of primary adrenal insufficiency, proceed to confirmatory testing 1
• Serum cortisol >500 nmol/L (18 mcg/dL) = adrenal insufficiency unlikely 1

Step 2: Confirmatory Testing When Equivocal

If morning cortisol is 250-500 nmol/L, perform cosyntropin (synacthen/tetracosactide) stimulation test: 1, 3

• Administer 0.25 mg cosyntropin intramuscularly or intravenously 1
• Measure serum cortisol at 30 and 60 minutes post-injection 1
• Peak cortisol <500 nmol/L (18 mcg/dL) = diagnostic of primary adrenal insufficiency 1
• Peak cortisol >550 nmol/L (20 mcg/dL) = normal adrenal function 1

Step 3: Etiologic Diagnosis

Once adrenal insufficiency is confirmed, determine the cause: 1

• Measure 21-hydroxylase autoantibodies (21OH-Ab) as first-line test—positive in ~85% of autoimmune Addison's disease in Western populations 1
• If 21OH-Ab negative, obtain CT imaging of adrenal glands to evaluate for hemorrhage, tuberculosis, metastases, or infiltrative disease 1
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to exclude adrenoleukodystrophy 1

Step 4: Assess Mineralocorticoid Status

Measure plasma renin activity (PRA) and serum aldosterone to evaluate mineralocorticoid deficiency: 1

• Elevated PRA with low aldosterone confirms mineralocorticoid deficiency requiring fludrocortisone replacement 1
• Also check serum DHEAS (typically low in primary adrenal insufficiency) 1

Critical Management Sequence

If both adrenal insufficiency and hypothyroidism are confirmed, ALWAYS initiate corticosteroid replacement at least 1 week before starting or increasing levothyroxine. 4, 2, 3 This prevents adrenal crisis, as thyroid hormone increases cortisol metabolism and can unmask or precipitate acute adrenal failure. 2, 3, 5

Corticosteroid Replacement Protocol

• Start hydrocortisone 15-25 mg daily in split doses (e.g., 10 mg upon waking, 5 mg at lunch, 5 mg early afternoon) 1
• Add fludrocortisone 50-200 mcg daily if mineralocorticoid deficiency confirmed 1
• Wait minimum 7 days after achieving stable corticosteroid replacement before initiating levothyroxine 4, 2

Special Considerations in Autoimmune Hypothyroidism

Patients with autoimmune thyroiditis (positive anti-TPO antibodies) have increased risk of concurrent autoimmune adrenal insufficiency (Addison's disease). 1 The presence of thyroid autoantibodies followed by development of hypothyroidism is frequently seen in primary adrenal insufficiency, and continuous surveillance for other autoimmune disorders is necessary. 1

Annual screening should include: 1

• Plasma glucose and HbA1c (screen for diabetes mellitus)
• Complete blood count (screen for anemia)
• Vitamin B12 levels (autoimmune gastritis common)
• Tissue transglutaminase 2 autoantibodies and total IgA (if episodic diarrhea, screen for celiac disease)

Common Pitfalls to Avoid

• Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—give IV hydrocortisone 100 mg immediately and secure blood samples for cortisol/ACTH before treatment if possible, but diagnosis can always be established later 1
• Do not misinterpret mildly elevated TSH (4-10 mIU/L) in untreated adrenal insufficiency as primary hypothyroidism—cortisol deficiency causes TSH elevation due to loss of cortisol's inhibitory effect on TSH production, which may normalize after corticosteroid replacement 1, 5
• Avoid starting levothyroxine in patients with unexplained hypotension, hyponatremia, or hyperpigmentation without first ruling out adrenal insufficiency—these features should trigger immediate adrenal evaluation 1
• Do not rely on random cortisol measurements—always obtain paired morning (8 AM) cortisol and ACTH for accurate assessment 1, 3

When Immediate Treatment is Required

If clinical suspicion of acute adrenal crisis exists (unexplained collapse, severe hypotension, vomiting/diarrhea, confusion), treat immediately: 1

• IV or IM hydrocortisone 100 mg immediately, followed by 100 mg every 6-8 hours 1
• Isotonic (0.9%) sodium chloride solution at initial rate of 1 L/hour until hemodynamic improvement 1
• Secure blood samples for cortisol and ACTH before first hydrocortisone dose if possible, but never delay treatment 1
• Seek underlying precipitant (infection, trauma, surgery) once treatment initiated 1