How to diagnose T3 to T4 conversion issues?

Diagnosing T3 to T4 Conversion Issues

To diagnose T3 to T4 conversion issues, you should measure TSH, free T4, and free T3 levels, looking for normal or elevated TSH with normal free T4 but low free T3 levels, which indicates impaired peripheral conversion of T4 to T3. 1

Key Laboratory Findings

Peripheral conversion issues typically present with the following pattern:

• Normal or elevated TSH
• Normal free T4 levels
• Low free T3 levels
• Elevated reverse T3 (rT3) in some cases
• Elevated rT3/T3 ratio 2

This pattern differs from primary hypothyroidism (elevated TSH + low free T4) and secondary hypothyroidism (low/normal TSH + low free T4) 1.

Physiological Background

Understanding the normal physiology helps identify conversion problems:

• The thyroid gland produces approximately 80% T4 and 20% T3 3
• About 80% of circulating T3 comes from peripheral conversion of T4 via type 1 deiodinase (DIO1) 3, 4
• T3 is the biologically active thyroid hormone with approximately 10-fold higher affinity for thyroid hormone receptors than T4 3
• Conversion occurs primarily in the liver and kidneys through the enzyme iodothyronine 5'-deiodinase 3

Clinical Scenarios Suggesting Conversion Issues

Look for these clinical situations where T4 to T3 conversion may be impaired:

1. Patients with persistent hypothyroid symptoms despite normal TSH on levothyroxine therapy
2. Acute or chronic illness - Extrathyroidal T4 conversion to T3 is decreased in various acute and chronic illnesses 5
3. Nutritional deficiencies - Selenium deficiency (selenium is required for deiodinase function) 1
4. Iron deficiency - Impairs thyroid metabolism 6
5. Certain medications - Beta-blockers, corticosteroids, amiodarone
6. Stress or trauma - During illness or stress, T4 to T3 conversion is often inhibited 3

Diagnostic Algorithm

1. Initial Testing:

   • Measure TSH, free T4, and free T3 simultaneously
   • Consider measuring reverse T3 (rT3) levels
   • Calculate rT3/T3 ratio (elevated in conversion issues) 2

2. Additional Testing:

   • Check for selenium and iron deficiencies 6
   • Evaluate liver and kidney function (major sites of T4 to T3 conversion)
   • Review medication list for drugs that may impair conversion

3. Interpretation:

   • Normal TSH + normal free T4 + low free T3 = likely conversion issue
   • Elevated rT3/T3 ratio provides further confirmation 2
   • The regression equation rT3/T3 = 0.015[T4] + 0.083 can help assess if the relationship is appropriate 2

Pitfalls to Avoid

1. Relying solely on TSH: TSH may be normal despite conversion issues 1

2. Ignoring T3 levels in levothyroxine-treated patients: While T3 testing isn't useful for assessing over-replacement 7, it's essential for identifying conversion problems

3. Failing to consider transport issues: In rare cases, T4 transport inhibition into T3-producing tissues (particularly the liver) can cause similar laboratory findings 8

4. Not accounting for diurnal variations: TSH levels can vary by up to 50% day-to-day 1

5. Overlooking non-thyroidal illness: Many acute and chronic conditions can temporarily impair T4 to T3 conversion 5

Treatment Considerations

If conversion issues are confirmed, treatment options may include:

• T3 supplementation (liothyronine) 9
• Combination T4/T3 therapy
• Addressing underlying causes (treating selenium or iron deficiency, reviewing medications)

The standard starting dose of liothyronine for mild hypothyroidism is 25 mcg daily, which may be increased by up to 25 mcg every 1-2 weeks until reaching a maintenance dose of 25-75 mcg daily 9.