What is the appropriate management for a patient with elevated Thyroid-Stimulating Hormone (TSH) levels and salt cravings, potentially indicating hypothyroidism or adrenal insufficiency?

High TSH and Salt Craving: Diagnostic Approach and Management

Immediate Priority: Rule Out Adrenal Insufficiency Before Treating Thyroid

Salt craving with elevated TSH requires urgent evaluation for concurrent adrenal insufficiency (Addison's disease), as starting thyroid hormone replacement before corticosteroids can precipitate life-threatening adrenal crisis. 1, 2

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Why This Combination is Critical

Salt craving is a cardinal symptom of primary adrenal insufficiency, occurring because mineralocorticoid deficiency causes renal sodium wasting 1. When adrenal insufficiency coexists with hypothyroidism (autoimmune polyglandular syndrome), initiating levothyroxine increases cortisol metabolism and can unmask severe cortisol deficiency, triggering adrenal crisis with hypotension, shock, and potential death 1.

In the presence of both adrenal insufficiency and hypothyroidism, steroids must always be started prior to thyroid hormone to avoid adrenal crisis. 1

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Diagnostic Algorithm

Step 1: Confirm Hypothyroidism and Assess Severity

• Measure TSH and free T4 to distinguish subclinical (normal free T4) from overt hypothyroidism (low free T4) 3
• If TSH >10 mIU/L, treatment is indicated regardless of symptoms due to ~5% annual progression risk to overt hypothyroidism 3
• Check anti-TPO antibodies to confirm autoimmune etiology (Hashimoto's thyroiditis), which predicts 4.3% annual progression risk versus 2.6% in antibody-negative patients 3

Step 2: Screen for Adrenal Insufficiency (MANDATORY)

Never delay this evaluation—adrenal crisis has high mortality if untreated. 1, 2

Morning Laboratory Tests (8 AM preferred):

• Paired serum cortisol and plasma ACTH 1, 2
• Basic metabolic panel (sodium, potassium, glucose) 1, 2
• Serum cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency 1, 2
• Serum cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion 1

Key Clinical Features Supporting Adrenal Insufficiency:

• Salt craving (specific for primary adrenal insufficiency with mineralocorticoid deficiency) 1, 2
• Hyponatremia (present in 90% of newly diagnosed cases) 2
• Hyperkalemia (present in only ~50% of cases—absence does NOT rule out diagnosis) 1, 2
• Hyperpigmentation (distinguishes primary from secondary adrenal insufficiency) 1
• Unexplained fatigue, weight loss, orthostatic hypotension 1, 2

Step 3: Confirmatory Testing if Initial Results Equivocal

• Perform 0.25 mg cosyntropin (synacthen) stimulation test 1, 2
• Measure cortisol at baseline, 30 minutes, and 60 minutes post-administration 1, 2
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>20 μg/dL) excludes adrenal insufficiency 2

Critical pitfall: Adrenal insufficiency can present with clinical picture nearly identical to SIADH (both cause euvolemic hypo-osmolar hyponatremia), so cosyntropin testing is medically necessary to distinguish these conditions 2

Step 4: Determine Etiology of Adrenal Insufficiency

• Measure 21-hydroxylase (anti-adrenal) autoantibodies—positive in ~85% of autoimmune Addison's disease 1, 2
• If antibodies negative, obtain CT imaging of adrenals to evaluate for hemorrhage, tumor, tuberculosis, or other structural causes 1, 2
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1

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Treatment Algorithm

If Adrenal Insufficiency is Confirmed or Strongly Suspected:

START CORTICOSTEROIDS FIRST—at least 1 week before initiating thyroid hormone. 1, 4, 5

Glucocorticoid Replacement:

• 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) 1, 2
• Alternative: Cortisone acetate 25-37.5 mg daily in divided doses 1
• For severe symptoms or suspected adrenal crisis: IV hydrocortisone 100 mg immediately, followed by 100 mg every 6-8 hours until recovered 1, 2

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only):

• Fludrocortisone 50-200 μg daily as single morning dose 1, 2
• Titrate based on blood pressure (supine and standing), salt cravings, and plasma renin activity 1, 2
• Advise unrestricted salt intake and salty foods 1

Patient Education and Safety:

• All patients must obtain and wear medical alert bracelet indicating adrenal insufficiency 1, 2
• Provide emergency injectable hydrocortisone 100 mg IM kit with self-injection training 2
• Educate on stress dosing: double or triple dose during illness, fever, or physical stress 2

After 1 Week of Corticosteroid Therapy, Initiate Thyroid Hormone:

Levothyroxine Dosing:

• For patients <70 years without cardiac disease: Start full replacement dose ~1.6 mcg/kg/day 3, 6
• For patients >70 years or with cardiac disease: Start 25-50 mcg/day and titrate gradually 3, 6
• For TSH >10 mIU/L: Treat regardless of symptoms 3
• For TSH 4.5-10 mIU/L: Consider treatment if symptomatic, positive anti-TPO antibodies, or planning pregnancy 3

Monitoring:

• Recheck TSH and free T4 every 6-8 weeks during dose titration 3, 6
• Target TSH 0.5-4.5 mIU/L with normal free T4 3, 6
• Once stable, monitor every 6-12 months or with symptom changes 3, 6

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If Adrenal Insufficiency is Excluded:

• Proceed directly with levothyroxine therapy as outlined above 3
• Investigate other causes of salt craving (e.g., medications, dietary habits, POTS, hyperaldosteronism) 1

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Special Considerations

Autoimmune Polyglandular Syndrome:

• Patients with autoimmune hypothyroidism have increased risk of concurrent autoimmune adrenal insufficiency 1, 2
• Annual screening for associated autoimmune conditions (diabetes, pernicious anemia, celiac disease) is warranted 2

Reversible Hypothyroidism in Adrenal Insufficiency:

• Adrenal insufficiency can cause reversible elevation of TSH with low or normal free T4 7, 5
• In some cases, thyroid function normalizes with corticosteroid replacement alone, without thyroid hormone 5
• This occurs because glucocorticoid deficiency impairs free water excretion and alters pituitary-thyroid axis feedback 7, 5, 8
• Recheck thyroid function 4-6 weeks after starting corticosteroids before committing to lifelong thyroid hormone replacement 5

Central Hypothyroidism Considerations:

• If TSH is low or inappropriately normal with low free T4, suspect central (secondary) hypothyroidism from pituitary/hypothalamic disease 1, 9
• Central hypothyroidism often coexists with central adrenal insufficiency (hypopituitarism) 1, 9
• Measure morning ACTH, cortisol, and other pituitary hormones (FSH, LH, testosterone/estradiol, prolactin) 1
• Consider MRI of sella with pituitary cuts 1

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Critical Pitfalls to Avoid

• Never start thyroid hormone before ruling out adrenal insufficiency in patients with salt craving or other suggestive symptoms—this can be fatal 1, 2, 4, 5
• Do not rely on absence of hyperkalemia to exclude adrenal insufficiency—it is present in only ~50% of cases 1, 2
• Do not assume hypothyroidism is the sole diagnosis when salt craving is present—this symptom is highly specific for mineralocorticoid deficiency 1, 2
• Treatment of suspected acute adrenal insufficiency should never be delayed for diagnostic procedures—give IV hydrocortisone 100 mg and 0.9% saline immediately if adrenal crisis is suspected 1, 2
• In confirmed coexisting conditions, both adrenal insufficiency and hypothyroidism appear to represent long-term sequelae requiring lifelong hormonal replacement in most cases 1