What causes decreased conversion of Thyroxine (T4) to Triiodothyronine (T3)?

Causes of Decreased Conversion of T4 to T3

The primary causes of decreased conversion of thyroxine (T4) to triiodothyronine (T3) include low energy availability, iron deficiency, certain medications, acute and chronic illnesses, and immune checkpoint inhibitors. Understanding these mechanisms is crucial for proper diagnosis and management of thyroid dysfunction.

Physiological and Nutritional Causes

Low Energy Availability

• Low energy availability states lead to decreased T3 and free T3 levels as a metabolic adaptation 1
• This is commonly seen in female athletes with relative energy deficiency in sport (RED-S)
• Occurs alongside other hormonal changes including decreased estradiol, progesterone, leptin, insulin, and IGF-1

Iron Deficiency

• Iron deficiency impairs T4 to T3 conversion through multiple mechanisms:
  • Impairs T4 synthesis 1
  • Reduces hepatic conversion of T4 to active T3 1
  • Shifts ATP production from oxidative phosphorylation to less efficient anaerobic pathways
  • Affects bone health through suppression of growth hormone and IGF-1

Medication-Induced Causes

Beta-Blockers

• Propranolol (non-selective beta-blocker) inhibits peripheral conversion of T4 to T3 2, 3
• This effect is dose-dependent and primarily seen with beta-blockers that have membrane-stabilizing activity
• Clinically used in hyperthyroidism management to reduce T3 levels, particularly in thyrotoxicosis and thyroid storm

Other Medications

• Amiodarone and other iodinated compounds (cholecystographic agents like ipodate and iopanoic acid) 4
• Propylthiouracil (PTU) - significantly inhibits type I 5'-deiodinase activity 5
• Glucocorticoids at high doses
• Anti-epileptic drugs (e.g., diphenylhydantoine) that induce hepatic metabolism 4

Disease States

Acute and Chronic Illness

• Many clinically euthyroid patients with severe chronic illnesses show:
  • Very low circulating T3 concentrations
  • Low-normal total T4
  • Elevated free T4
  • Normal or subnormal TSH 6
• This pattern, known as "sick euthyroid syndrome" or "non-thyroidal illness syndrome," results from inhibition of extrathyroidal conversion of T4 to T3 7
• When T4 conversion to T3 is impaired, serum concentrations of biologically inactive reverse T3 (rT3) increase

Immune-Related Endocrinopathies

• Immune checkpoint inhibitors (ICPIs) can cause thyroid dysfunction in 6-20% of patients 1
• Thyroiditis from ICPIs can progress from initial thyrotoxicosis to permanent hypothyroidism
• Hypophysitis (particularly with anti-CTLA4 therapy) can affect the pituitary-thyroid axis 1

Metabolic Considerations

Liver Disease

• The liver is a major site of T4 to T3 conversion through type 1 deiodinase (DIO1) 1
• Liver dysfunction can significantly impair this conversion process
• Resmetirom (a thyroid hormone receptor-β agonist) actually increases T4 to T3 conversion through upregulation of DIO1 in the liver 1

Clinical Implications

• Regular monitoring of thyroid function is recommended in patients on medications affecting thyroid hormone metabolism 2
• In patients with suspected conversion issues, both T4 and T3 levels should be measured
• Treatment approaches depend on the underlying cause:
  • For nutritional causes: address energy and iron deficiencies
  • For medication-induced causes: consider medication adjustments when possible
  • For illness-related causes: treat the underlying condition

Diagnostic Approach

When decreased T4 to T3 conversion is suspected:

1. Measure complete thyroid panel (TSH, free T4, free T3, reverse T3 when available)
2. Evaluate for nutritional deficiencies, particularly iron status
3. Review medication list for agents known to affect conversion
4. Assess for underlying acute or chronic illnesses
5. Consider pituitary function testing if central hypothyroidism is suspected

Understanding these mechanisms helps clinicians properly interpret thyroid function tests and manage patients with thyroid dysfunction appropriately.