What is central hypothyroidism?

What is Central Hypothyroidism?

Central hypothyroidism is a rare thyroid disorder caused by insufficient stimulation of an otherwise normal thyroid gland due to inadequate TSH secretion from the pituitary (secondary) or hypothalamus (tertiary), resulting in low free T4 with inappropriately low or normal TSH levels. 1, 2, 3

Pathophysiology and Causes

Central hypothyroidism results from dysfunction at the hypothalamic or pituitary level, preventing adequate TSH production or secretion despite a structurally normal thyroid gland 2, 4. This distinguishes it fundamentally from primary hypothyroidism, where the thyroid itself is diseased 5.

Acquired Causes (Most Common in Adults)

• Pituitary macroadenomas represent the most frequent cause in adults, either through mass effect or following surgical resection 3, 6
• Pituitary surgery or cranial irradiation for tumors or hematological malignancies commonly results in central hypothyroidism 3
• Immune checkpoint inhibitor therapy, particularly ipilimumab, causes hypophysitis with central hypothyroidism in up to 17% of patients at higher doses, with median onset at 14.5 weeks 7, 1
• Traumatic brain injury, subarachnoid hemorrhage, and Sheehan syndrome are recognized causes 4
• Lymphocytic hypophysitis can present with central hypothyroidism alongside other pituitary hormone deficiencies 4

Congenital/Genetic Causes

• Mutations in genes including TRHR, POU1F1, PROP1, HESX1, SOX3, LHX3, LHX4, and TSHB are associated with congenital central hypothyroidism 4, 6
• Biallelic TSHβ mutations cause neonatal central hypothyroidism with more profound thyroid hormone deficiency 5
• The genetic basis may be underrecognized, as recent data suggest heritable causes in pediatric and adult patients without apparent pituitary lesions 6

Prevalence and Epidemiology

• Central hypothyroidism has an estimated prevalence of 1 in 80,000 to 1 in 120,000, making it approximately 1000-fold rarer than primary hypothyroidism 3, 5
• The true frequency may be underestimated due to diagnostic challenges and reliance on TSH-reflex screening strategies that miss cases with normal TSH 2, 6

Clinical Presentation

The clinical manifestations of central hypothyroidism are typically milder than those observed in primary hypothyroidism, as the thyroid hormone deficiency is rarely as profound. 2, 5

Key Clinical Features

• Fatigue and peripheral edema are the most specific clinical features distinguishing central from primary hypothyroidism 3
• Patients frequently present with multiple pituitary hormone deficiencies rather than isolated thyroid dysfunction 4, 5
• Central diabetes insipidus occurs in 25-50% of patients with hypophysitis, often preceding the diagnosis by years or decades 7
• Headaches (85%) and visual changes may indicate pituitary mass effect or hypophysitis 7

Associated Endocrinopathies

• Central adrenal insufficiency occurs in >75% of patients with hypophysitis and must be identified before starting thyroid hormone replacement 7, 1
• Growth hormone, gonadotropin, and corticotropin deficiencies commonly coexist with central hypothyroidism 7
• Hyperprolactinemia can be seen in 15-30% of patients with pituitary stalk involvement 7

Diagnostic Approach

The diagnosis of central hypothyroidism requires demonstrating low free T4 in the presence of low-to-normal TSH concentrations—a biochemical pattern that distinguishes it from primary hypothyroidism. 1, 2, 3

Critical Diagnostic Steps

• Measure both TSH and free T4 simultaneously, as low TSH alone can indicate either hyperthyroidism or central hypothyroidism 1
• TSH levels in central hypothyroidism can be low, normal, or even slightly elevated despite severe hypothyroidism, making TSH unreliable for diagnosis 1, 4, 5
• Free T4 levels are typically low-normal or subnormal, confirming inadequate thyroid hormone production 3, 4
• Thyrotropin-releasing hormone (TRH) stimulation testing can confirm the diagnosis when biochemical results are equivocal 3

Imaging and Additional Workup

• MRI of the sella with pituitary cuts is essential to identify structural lesions, with findings including pituitary enlargement, stalk thickening, suprasellar convexity, and heterogeneous enhancement 7
• Morning cortisol and ACTH levels must be checked immediately before starting thyroid hormone replacement to rule out secondary adrenal insufficiency 1
• Assess all other pituitary hormone axes (gonadotropins, growth hormone, prolactin) as isolated central hypothyroidism is uncommon 7, 5

Common Diagnostic Pitfalls

• The "TSH-reflex strategy" (measuring TSH alone, with free T4 only if TSH is abnormal) systematically misses central hypothyroidism cases with normal TSH 2, 6
• Methodological interference in free T4 or TSH assays can produce misleading results 2
• Concurrent systemic illness (nonthyroidal illness syndrome) can cause low free T4 with normal TSH, mimicking central hypothyroidism 2
• Neonatal screening programs based solely on TSH measurement without T4 will miss congenital central hypothyroidism 2
• Heterophilic antibodies can cause assay interference, leading to falsely normal or elevated TSH readings 2

Treatment Principles

Levothyroxine replacement is the treatment for central hypothyroidism, but critical safety considerations and monitoring strategies differ fundamentally from primary hypothyroidism management. 1, 3, 4

Critical Safety Consideration: Rule Out Adrenal Insufficiency First

• Starting thyroid hormone before ruling out adrenal insufficiency can precipitate life-threatening adrenal crisis, as thyroid hormone increases cortisol metabolism. 1
• Hydrocortisone must be started several days before initiating levothyroxine when multiple pituitary hormones are deficient 1
• Maintenance hydrocortisone dosing is 10-20 mg orally in the morning and 5-10 mg in early afternoon 1
• For severe symptoms or suspected adrenal crisis, IV hydrocortisone 100 mg with at least 2 liters normal saline should be administered immediately 1

Levothyroxine Dosing Strategy

• Start levothyroxine only after corticosteroid replacement is established 1
• For patients under 70 without cardiac disease, initiate approximately 1.6 mcg/kg/day 1
• For elderly patients or those with cardiac disease, start conservatively at 25-50 mcg/day 1
• Doses may need to be higher than empirically used, adjusted according to age and other hormone deficiencies 4

Monitoring and Dose Titration

• Free T4 levels, not TSH, must be used for monitoring and dose adjustments in central hypothyroidism. 1, 3, 6
• Target free T4 concentrations in the upper half of the normal reference range 1, 3, 4
• Recheck free T4 in 6-8 weeks after dose adjustments 1
• Adequate thyroid hormone replacement is associated with suppression of residual TSH secretion, making TSH unreliable for monitoring 5, 6
• Normal TSH levels during treatment may paradoxically indicate thyroxine under-replacement in central hypothyroidism patients 6

Special Considerations

• Growth hormone or sex steroid replacement may unmask latent central hypothyroidism or increase levothyroxine requirements 4, 6
• All patients require education on stress dosing and a medical alert bracelet for adrenal insufficiency 1
• Endocrine consultation is required prior to surgery or procedures for stress-dose planning 1

Key Distinguishing Features from Primary Hypothyroidism

• TSH is elevated in primary hypothyroidism but low-to-normal in central hypothyroidism 2, 3, 5
• Thyroid hormone deficiency is typically milder in central hypothyroidism 2, 5
• Central hypothyroidism usually occurs with other pituitary hormone deficiencies, while primary hypothyroidism is isolated 4, 5
• Levothyroxine replacement suppresses residual TSH in central hypothyroidism but normalizes elevated TSH in primary hypothyroidism 5, 6
• Free T4, not TSH, must guide treatment monitoring in central hypothyroidism 1, 6