What are the concerns and appropriate next steps for a 60-year-old woman with fatigue, three-month diffuse facial and neck hyperpigmentation, a morning serum cortisol of 7.8 µg/dL, low-normal adrenocorticotropic hormone (ACTH) of 17 pg/mL, low dehydroepiandrosterone sulfate (DHEA‑S) of 61 µg/dL, suppressed thyroid‑stimulating hormone (TSH) of 0.21 µIU/mL and elevated free thyroxine (free T4)?

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Urgent Concerns: Probable Primary Adrenal Insufficiency with Concurrent Hyperthyroidism

This patient has multiple red flags for primary adrenal insufficiency (Addison's disease) that require immediate evaluation and likely treatment before addressing the thyroid abnormality. The combination of diffuse hyperpigmentation over 3 months, fatigue, borderline-low morning cortisol (7.8 µg/dL), low-normal ACTH (17 pg/mL), and very low DHEA-S (61 µg/dL) strongly suggests evolving or partially compensated adrenal insufficiency 1, 2.

Critical Diagnostic Concerns

The Hyperpigmentation is the Key Clinical Finding

  • Diffuse facial and neck hyperpigmentation developing over 3 months in a 60-year-old woman is highly suspicious for primary adrenal insufficiency, as elevated ACTH stimulates melanocytes and causes characteristic darkening of skin creases, scars, and sun-exposed areas 1, 3, 4.

  • The morning cortisol of 7.8 µg/dL falls in the indeterminate range (5-10 µg/dL) where adrenal insufficiency cannot be excluded, and this level is concerning when paired with hyperpigmentation and fatigue 1, 2.

  • The ACTH of 17 pg/mL appears "normal" but is inappropriately low for a cortisol of 7.8 µg/dL—in true primary adrenal insufficiency with cortisol this low, ACTH should be markedly elevated (often >100 pg/mL), suggesting this may represent early or partially compensated disease 1, 2, 5.

  • DHEA-S of 61 µg/dL is severely low and strongly supports adrenal dysfunction, as DHEA-S is produced exclusively by the adrenal cortex and drops early in adrenal insufficiency 1, 2.

The Thyroid Abnormality Complicates the Picture

  • TSH 0.21 mIU/L with elevated free T4 indicates overt hyperthyroidism (likely Graves' disease), which can rarely cause hyperpigmentation through elevated ACTH or anti-TSH receptor antibodies 6.

  • However, hyperpigmentation from hyperthyroidism alone is extremely rare and typically resolves with treatment of the thyroid disorder—the persistence over 3 months with fatigue makes adrenal insufficiency far more likely 6.

  • Critically, starting or optimizing thyroid hormone replacement in a patient with undiagnosed adrenal insufficiency can precipitate life-threatening adrenal crisis by increasing cortisol metabolism 1, 7, 8.

Immediate Next Steps (Algorithmic Approach)

Step 1: Confirm or Exclude Adrenal Insufficiency BEFORE Treating Hyperthyroidism

Perform a cosyntropin (ACTH) stimulation test immediately:

  • Administer 0.25 mg (250 µg) cosyntropin IV or IM 1.
  • Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1.
  • Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency 1.
  • Peak cortisol >550 nmol/L (>20 µg/dL) excludes adrenal insufficiency 1.

If the stimulation test cannot be performed immediately and clinical suspicion is high:

  • Draw baseline cortisol and ACTH before any treatment 1.
  • Do NOT delay treatment if the patient shows signs of impending adrenal crisis (hypotension, hyponatremia, altered mental status, severe vomiting) 1.
  • Administer hydrocortisone 100 mg IV immediately plus 0.9% saline infusion at 1 L/hour 1.

Step 2: Check for Autoimmune Etiology and Associated Conditions

  • Measure 21-hydroxylase (anti-adrenal) autoantibodies to identify autoimmune adrenalitis, which accounts for ~85% of primary adrenal insufficiency in Western populations 1, 4.

  • Check anti-thyroid peroxidase (anti-TPO) antibodies and anti-TSH receptor antibodies (TRAb) to confirm Graves' disease and assess for polyglandular autoimmune syndrome type 2 (PAS-2), which combines Addison's disease with autoimmune thyroid disease 4, 6.

  • Screen for other autoimmune conditions: measure fasting glucose or HbA1c (type 1 diabetes), tissue transglutaminase antibodies (celiac disease), and vitamin B12 (pernicious anemia) 1, 4.

Step 3: Assess Electrolytes and Volume Status

  • Check serum sodium, potassium, glucose, and creatinine 1, 2.
  • Hyponatremia occurs in 90% of newly diagnosed adrenal insufficiency cases 1.
  • Hyperkalemia is present in only ~50% of cases, so its absence does NOT exclude adrenal insufficiency 1.
  • Hypoglycemia and elevated creatinine (prerenal azotemia) may also be present 1.

Treatment Algorithm Based on Test Results

If Adrenal Insufficiency is Confirmed (Peak Cortisol <18 µg/dL):

Initiate glucocorticoid replacement immediately:

  • Hydrocortisone 15-25 mg daily in divided doses (e.g., 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) to mimic diurnal cortisol rhythm 1, 2.
  • Alternative: Prednisone 3-5 mg daily (hydrocortisone 20 mg ≈ prednisone 5 mg) 9, 1.

Add mineralocorticoid replacement for primary adrenal insufficiency:

  • Fludrocortisone 0.05-0.1 mg daily, titrated based on blood pressure, orthostatic symptoms, and plasma renin activity 1, 2, 3.
  • Monitor for signs of over-replacement (edema, hypertension) or under-replacement (salt craving, orthostatic hypotension) 1, 3.

Patient education and safety measures (mandatory):

  • Teach stress-dosing: double or triple glucocorticoid dose during illness, fever, or physical stress 1, 2.
  • Prescribe injectable hydrocortisone 100 mg IM kit with self-injection training for adrenal crisis 1, 2.
  • Provide medical alert bracelet or necklace indicating adrenal insufficiency 1, 2.

Wait at least 1 week after starting glucocorticoid replacement before addressing hyperthyroidism:

  • Starting thyroid treatment (methimazole or beta-blockers) before adequate glucocorticoid coverage can precipitate adrenal crisis by increasing cortisol metabolism 1, 7, 8.
  • Once adrenal replacement is stable, treat hyperthyroidism with methimazole 15-30 mg daily and propranolol 20-40 mg TID for symptom control 6.

If Adrenal Insufficiency is Excluded (Peak Cortisol >20 µg/dL):

Proceed with treatment of hyperthyroidism:

  • Initiate methimazole 15-30 mg daily for Graves' disease 6.
  • Add propranolol 20-40 mg TID for symptom control (tachycardia, tremor, anxiety) 6.
  • Monitor TSH and free T4 every 4-6 weeks until euthyroid 7.

Investigate alternative causes of hyperpigmentation:

  • Consider drug-induced pigmentation (review all medications).
  • Evaluate for hemochromatosis (serum ferritin, transferrin saturation).
  • Consider dermatology referral if hyperpigmentation persists despite thyroid normalization 6.

Common Pitfalls and How to Avoid Them

Pitfall 1: Treating Hyperthyroidism Before Ruling Out Adrenal Insufficiency

  • Never start methimazole, beta-blockers, or thyroid hormone adjustments until adrenal function is confirmed normal 1, 7, 8.
  • Thyroid hormone increases cortisol metabolism, and in a patient with marginal adrenal reserve, this can trigger adrenal crisis 1, 8.

Pitfall 2: Dismissing "Normal" ACTH as Excluding Adrenal Insufficiency

  • An ACTH of 17 pg/mL is inappropriately low for a cortisol of 7.8 µg/dL—in true primary adrenal insufficiency, ACTH should be >100 pg/mL 1, 2.
  • This pattern suggests either early/partial adrenal insufficiency or a mixed picture (e.g., pituitary involvement) 1, 5.
  • The cosyntropin stimulation test is essential to definitively rule in or rule out adrenal insufficiency 1.

Pitfall 3: Relying on Electrolytes to Exclude Adrenal Insufficiency

  • Hyperkalemia is absent in ~50% of adrenal insufficiency cases 1.
  • Hyponatremia may be only mildly reduced or absent 1.
  • Do not use normal electrolytes to exclude adrenal insufficiency in a patient with hyperpigmentation and fatigue 1.

Pitfall 4: Attributing Hyperpigmentation Solely to Hyperthyroidism

  • Hyperpigmentation from Graves' disease is extremely rare and typically resolves with thyroid treatment 6.
  • Diffuse, progressive hyperpigmentation over 3 months with fatigue is Addison's disease until proven otherwise 1, 3, 4.

Pitfall 5: Delaying Treatment in Suspected Adrenal Crisis

  • If the patient develops hypotension, altered mental status, severe vomiting, or shock, do NOT wait for test results 1.
  • Administer hydrocortisone 100 mg IV immediately plus aggressive saline resuscitation 1.
  • Draw cortisol and ACTH before treatment if possible, but never delay treatment for diagnostic procedures 1.

Why This Patient Likely Has Primary Adrenal Insufficiency

Supporting Evidence:

  • Hyperpigmentation: Classic for elevated ACTH in primary adrenal insufficiency 1, 3, 4.
  • Fatigue and weight loss: Present in 50-95% and 43-73% of adrenal insufficiency cases, respectively 2.
  • Low-normal cortisol (7.8 µg/dL): Falls in the indeterminate range requiring stimulation testing 1, 2.
  • Very low DHEA-S (61 µg/dL): Strongly supports adrenal cortex dysfunction 1, 2.
  • Inappropriately low ACTH (17 pg/mL): Suggests partial or early adrenal failure 1, 5.

Contradictory Evidence:

  • ACTH is not markedly elevated: In classic Addison's disease, ACTH is typically >100 pg/mL 1, 2.
  • Possible explanation: This may represent partially compensated hypoadrenalism, where cortisol is maintained in the low-normal range by moderately elevated ACTH, but the patient remains symptomatic and at risk for crisis 5.

Summary of Immediate Actions

  1. Perform cosyntropin stimulation test to confirm or exclude adrenal insufficiency 1.
  2. Check 21-hydroxylase antibodies, anti-TPO antibodies, TRAb, electrolytes, and glucose 1, 4, 6.
  3. If adrenal insufficiency is confirmed: Start hydrocortisone 15-25 mg daily + fludrocortisone 0.05-0.1 mg daily, educate on stress-dosing, and provide emergency injectable hydrocortisone 1, 2, 3.
  4. Wait at least 1 week after starting glucocorticoid replacement before treating hyperthyroidism 1, 7, 8.
  5. If adrenal insufficiency is excluded: Proceed with methimazole and propranolol for Graves' disease 6.
  6. Refer to endocrinology for long-term management of both conditions 1.

References

1
Guideline

Diagnosing Adrenal Insufficiency in Hypo-osmolar Hyponatremia

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

7
Guideline

Initial Treatment for Elevated TSH

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

9
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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