What is T4 (thyroxine) resistance?

T4 Resistance (Thyroid Hormone Resistance)

Definition

T4 resistance, more accurately termed thyroid hormone resistance, is a rare genetic disorder where the body's tissues fail to respond normally to thyroid hormones despite adequate or elevated circulating levels of T4 and T3. 1

Key Biochemical Pattern

The hallmark laboratory finding is:

• Elevated serum T4 and T3 levels
• Normal or inappropriately elevated TSH (not suppressed as would be expected with high thyroid hormones) 1, 2
• This pattern is paradoxical because normally elevated thyroid hormones should suppress TSH through negative feedback 1

Clinical Subtypes

Generalized Resistance to Thyroid Hormone (GRTH)

• Most common form where resistance occurs in both the pituitary gland and peripheral tissues 1
• Patients are typically clinically euthyroid (no symptoms of hyper- or hypothyroidism) despite abnormal labs 1
• No treatment is usually required since tissues are uniformly resistant 1

Selective Pituitary Resistance (PRTH)

• Resistance primarily in the pituitary but not in peripheral tissues 1
• Patients are clinically thyrotoxic (symptomatic hyperthyroidism) with elevated thyroid hormones and inappropriately normal/elevated TSH 1
• Treatment is necessary but current therapeutic options are not completely satisfactory 1

Selective Peripheral Resistance (PerRTH)

• Extremely rare form with resistance in peripheral tissues but not the pituitary 1
• Patients are clinically hypothyroid despite normal thyroid hormone and TSH levels 1
• Improves with thyroid hormone administration 1

Genetic Basis

In most studied cases, GRTH results from mutations in the thyroid hormone receptor beta gene (THRB) causing amino acid substitutions or deletions in the hormone-binding domain of the receptor 1, 2

The genetic screening approach when resistance is suspected:

• First screen THRB gene (accounts for 26% of cases with discordant TSH/thyroid hormone levels) 2
• Consider screening genes for thyroid hormone transport proteins (ALB, TTR, SERPINA7) as these can mimic resistance 2
• Additional genes to consider: THRA, SECISBP2, SLC16A 2

Critical Diagnostic Pitfalls

Distinguish from Analytical Interference

Before pursuing genetic testing, repeat thyroid function tests using a different immunoassay platform to rule out laboratory interference, which accounts for approximately 24-26% of cases with discordant results 2

Common causes of false elevation mimicking resistance:

• Variants in thyroid hormone transport proteins (albumin, transthyretin, thyroxine-binding globulin) 2
• Heterophile antibodies or other assay interference 2
• Medications affecting thyroid function tests (dopamine, glucocorticoids, amiodarone) 3

Avoid Misdiagnosis

These disorders are often misdiagnosed and inappropriately treated 1:

• GRTH patients may be incorrectly treated for hyperthyroidism based on elevated T4/T3 alone
• Patients may undergo unnecessary thyroid ablation or receive antithyroid drugs when no treatment is needed 1

Recommended Diagnostic Algorithm

1. Confirm persistent abnormality: Repeat testing in 4-6 weeks using a different assay platform 3, 2
2. Assess clinical status: Determine if patient is euthyroid, thyrotoxic, or hypothyroid 1
3. Measure free T4, free T3, and TSH simultaneously 2
4. If pattern persists, proceed with genetic testing: Start with THRB gene sequencing 2
5. Screen for transport protein variants if THRB is negative 2

Clinical Significance

Approximately 24% of cases with discordant thyroid function tests remain unexplained even after comprehensive genetic and analytical evaluation 2, emphasizing that this remains an incompletely understood area requiring specialized endocrine expertise.