How do you diagnose thyroid hormone resistance?

Diagnosing Thyroid Hormone Resistance

Thyroid hormone resistance (THR) is diagnosed by finding elevated free T4 and free T3 levels with normal or slightly elevated TSH levels in the absence of a TSH-secreting pituitary adenoma. 1

Key Diagnostic Features

Laboratory Findings

• Elevated serum free thyroxine (FT4) and free triiodothyronine (FT3)
• Normal or slightly elevated thyroid-stimulating hormone (TSH)
• Altered T4:T3 ratio (low FT4 with high FT3) 2

Clinical Presentation

• Goiter without typical symptoms of thyroid hormone excess 1
• Most patients are clinically euthyroid despite abnormal laboratory values 3
• Some patients may present with:
  • Growth retardation
  • Mild-to-moderate mental retardation
  • Mild skeletal dysplasia
  • Constipation
  • Specific facial features (round, somewhat coarse and flat face)
  • Macrocephaly 2

Diagnostic Algorithm

1. Initial Laboratory Testing:

   • Measure TSH, free T4, and free T3 levels
   • Look for the characteristic pattern: elevated FT4/FT3 with normal or elevated TSH 1, 3

2. Differential Diagnosis:

   • Rule out TSH-secreting pituitary adenoma (TSHoma)
     • Family history of THR supports diagnosis of resistance syndrome
     • MRI of pituitary may be needed to exclude adenoma 1
   • Rule out assay interference (thyroid hormone antibodies)
     • Repeat testing with different assay methods

3. Classification of THR:

   • Generalized resistance (GRTH): resistance in both pituitary and peripheral tissues
   • Selective pituitary resistance (PRTH): resistance in pituitary but not peripheral tissues
   • Selective peripheral resistance (PerRTH): resistance in peripheral tissues but not pituitary 3

4. Genetic Testing:

   • Sequence the thyroid hormone receptor beta (THRB) gene
     • Mutations in THRB account for approximately 85% of cases 2
   • If THRB testing is negative, consider sequencing the thyroid hormone receptor alpha (THRA) gene
     • THRA mutations present with a distinct phenotype 2

Important Clinical Considerations

Potential Comorbidities

• THR can coexist with chronic thyroiditis/autoimmune thyroid disease
  • Check for anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies 4
• Attention deficit disorder and cognitive issues ("foggy brain") may be present 5

Phenotypic Variability

• Clinical presentation varies significantly among individuals with the same mutation
• Different tissues may respond differently to thyroid hormone in the same individual 5
• Genotype-phenotype correlation exists:
  • Missense mutations typically cause milder phenotypes
  • Truncating mutations result in more severe phenotypical effects 2

Common Pitfalls to Avoid

1. Misdiagnosis as hyperthyroidism - Patients with THR are often misdiagnosed with hyperthyroidism due to elevated thyroid hormone levels, leading to inappropriate treatment 3

2. Overlooking family history - Family history is crucial in distinguishing THR from TSH-secreting pituitary adenoma 1

3. Focusing solely on laboratory values - Clinical assessment is essential as laboratory values alone can be misleading; many patients are clinically euthyroid despite abnormal lab results 3

4. Inappropriate treatment - Most patients with generalized THR require no treatment; inappropriate treatment with anti-thyroid medications can worsen hypothyroid symptoms 3

5. Missing variants of unknown significance - Emerging evidence suggests that variants of unknown significance in thyroid hormone receptor genes may have clinical relevance 5

THR is likely more common than generally recognized and should be considered in patients with elevated thyroid hormone levels and non-suppressed TSH, especially when there is a family history of similar thyroid abnormalities.