What is thyroid resistance?

Thyroid Hormone Resistance: Definition and Clinical Significance

Thyroid hormone resistance (also called resistance to thyroid hormone or RTH) is a rare genetic syndrome characterized by reduced tissue sensitivity to thyroid hormone, resulting in elevated free T4 and T3 levels with inappropriately normal or elevated TSH—the opposite pattern of typical thyroid dysfunction. 1

Core Pathophysiology

Thyroid hormone resistance represents a fundamental defect in how the body's tissues respond to circulating thyroid hormones, despite adequate or elevated hormone levels. 2 The syndrome occurs due to:

• Mutations in thyroid hormone receptor genes (primarily the THRB gene encoding thyroid hormone receptor β) that impair the receptor's ability to bind thyroid hormone or activate gene transcription 1
• Autosomal dominant inheritance pattern in most familial cases, though sporadic mutations occur 3
• Variable tissue resistance creating a dysbalance between tissues expressing different receptor isoforms 1

Clinical Classification

RTHβ (Resistance to Thyroid Hormone Beta)

This is the most common form, caused by mutations in the THRB gene. 1 Key features include:

• Goiter (thyroid enlargement) 1
• Sinus tachycardia (reflecting overstimulation of tissues expressing thyroid hormone receptor α) 1
• Attention deficit hyperactivity disorder 1
• Elevated free T4 and T3 with non-suppressed TSH (the biochemical hallmark) 1
• Generally euthyroid clinical status despite abnormal laboratory values 2

RTHα (Resistance to Thyroid Hormone Alpha)

Recently identified form caused by THRA gene mutations. 1 Characterized by:

• Mental retardation of variable severity 1
• Short stature with decreased subischial leg length 1
• Chronic constipation 1
• Bradycardia (opposite of RTHβ) 1

Historical Subtypes (Now Recognized as Spectrum)

The literature previously described three patterns that are now understood to represent variable expression of the same genetic disorder: 4

• Generalized resistance (GRTH): Resistance in both pituitary and peripheral tissues, patients typically euthyroid 2
• Selective pituitary resistance (PRTH): Pituitary resistant but peripheral tissues sensitive, patients clinically thyrotoxic 2
• Selective peripheral resistance (PerRTH): Extremely rare, peripheral tissues resistant but pituitary sensitive, patient clinically hypothyroid 2

Diagnostic Hallmarks

The biochemical signature is elevated free T4 and free T3 with inappropriately normal or elevated TSH—a pattern that would be impossible in normal thyroid physiology. 5

Critical diagnostic features:

• Family history of similar thyroid function abnormalities (present in majority of cases) 3
• Normal TSH response to TRH that cannot be suppressed by T3 administration 4
• Absence of TSH-secreting pituitary adenoma on imaging (the main differential diagnosis) 5
• Goiter without typical symptoms of thyrotoxicosis in most cases 5

Key Clinical Pitfalls

The most common error is misdiagnosing RTH as primary hyperthyroidism and inappropriately treating with antithyroid drugs, radioactive iodine, or thyroidectomy—interventions that worsen the condition. 3 Additional pitfalls include:

• Confusing RTH with TSH-secreting pituitary adenoma: Family history and normal pituitary imaging distinguish RTH 5
• Treating based on laboratory values alone: Most patients with generalized resistance are clinically euthyroid and require no treatment 2
• Failing to recognize variable clinical expression: Even within the same family with identical mutations, clinical presentation varies from euthyroid to thyrotoxic 4

Management Approach

Most patients with generalized thyroid hormone resistance require no treatment, as they are clinically euthyroid despite abnormal laboratory values. 2 When treatment is necessary:

• For thyrotoxic symptoms (selective pituitary resistance): Options include L-T3, TRIAC (3',5-triiodothyroacetic acid), or D-T4, though no therapy is completely satisfactory 2, 5
• For hypothyroid symptoms (rare peripheral resistance): Thyroid hormone supplementation may be beneficial 2
• Avoid all measures to lower thyroid hormone levels in asymptomatic patients with generalized resistance 3

Prevalence and Recognition

RTH is more common than generally recognized and is frequently misdiagnosed, leading to inappropriate and potentially harmful treatment. 2 The syndrome affects males and females equally and should be suspected whenever elevated thyroid hormones coexist with non-suppressed TSH. 3