What is the most common cause of elevated Thyroid-stimulating hormone (TSH) and elevated Thyroxine (T4) levels?

Most Common Cause of Elevated TSH and Elevated T4

The most common cause of elevated TSH with elevated T4 is thyroid hormone resistance syndrome, particularly resistance to thyroid hormone beta (RTH-β). 1, 2

Understanding Thyroid Hormone Resistance

Thyroid hormone resistance is characterized by:

• Elevated serum levels of free T4 and T3
• Inappropriately normal or elevated TSH levels
• Variable clinical presentation ranging from asymptomatic to symptoms of both hypo- and hyperthyroidism

This pattern contradicts the typical negative feedback loop where elevated thyroid hormones should suppress TSH production. In thyroid hormone resistance, target tissues show reduced responsiveness to thyroid hormones.

Pathophysiology

• Most commonly caused by mutations in the thyroid hormone receptor beta gene (TR-β) 1
• Usually involves mutation in only one allele, producing a dominantly inherited condition 1
• The mutant receptor blocks the action of the normal allele (dominant negative effect)

Clinical Variants

There are several patterns of resistance:

1. Global resistance - affects both peripheral tissues and pituitary (most common)
2. Selective pituitary resistance - primarily affects the pituitary 3, 4
3. Selective peripheral resistance - primarily affects peripheral tissues 5

Clinical Presentation

Patients with thyroid hormone resistance often present with:

• Normal metabolic status (eumetabolic) despite abnormal lab values 2
• Goiter (thyroid enlargement) 2
• Variable symptoms depending on the pattern and degree of resistance
• May have developmental issues including delayed bone maturation, learning disabilities, or hearing defects 2

Diagnostic Approach

1. Laboratory findings:

   • Elevated free T4 and T3
   • Normal or elevated TSH (inappropriate for the T4/T3 levels)
   • Normal thyroid hormone metabolism 2

2. Differential diagnosis:

   • TSH-secreting pituitary adenoma (can be ruled out with MRI and alpha subunit testing) 3
   • Laboratory assay interference
   • Familial dysalbuminemic hyperthyroxinemia

3. Confirmatory testing:

   • TRH stimulation test (TSH increases after TRH administration despite high T4) 3
   • Genetic testing for TR-β mutations

Management Considerations

Treatment decisions depend on individual patient characteristics 1:

• Many patients require no treatment if they are clinically euthyroid
• Patients with hypothyroid symptoms may benefit from thyroid hormone supplementation
• Patients with hyperthyroid symptoms may require beta-blockers or selective thyroid hormone analogs

Important Cautions

• Avoid treatments aimed at lowering thyroid hormone levels (antithyroid drugs, radioiodine, surgery) as these can worsen the condition by further stimulating TSH and causing goiter enlargement 2
• Standard treatments for hyperthyroidism are generally ineffective and potentially harmful in this condition

Clinical Pearls

• The diagnosis is often missed initially, with patients incorrectly treated for hyperthyroidism 3, 5
• The condition is equally common in males and females 2
• Inheritance is typically autosomal dominant
• The severity of resistance may vary between different tissues in the same individual 5
• Patients may appear clinically euthyroid despite markedly abnormal laboratory values

Remember that thyroid hormone resistance is a diagnosis of exclusion and requires careful clinical evaluation to distinguish it from other causes of inappropriate TSH secretion.