What are the causes and treatment options for low Thyroxine (T4) with normal Thyroid-Stimulating Hormone (TSH) levels?

Causes of Low T4 with Normal TSH

The most common cause of low T4 with normal TSH is central hypothyroidism, which requires treatment with levothyroxine replacement therapy guided by free T4 levels rather than TSH. 1

Causes of Low T4 with Normal TSH

1. Central (Secondary) Hypothyroidism

   • Pituitary or hypothalamic disorders 1
   • Tumors, surgery, radiation, trauma to pituitary/hypothalamus 1
   • Immune checkpoint inhibitor therapy 1

2. Iodine Deficiency

   • Causes intrathyroidal autoregulatory changes leading to increased T3 production at expense of T4 2
   • Results in low serum T4, normal/slightly elevated T3, and normal TSH 2

3. Laboratory Interference

   • Heterophile antibodies can cause false results 3
   • Assay interference in commonly used TSH or thyroid hormone immunoassays 4

4. Thyroxine-Binding Globulin (TBG) Deficiency

   • Hereditary genetic disorder causing low total T4 but normal free T4 and TSH 3
   • No clinical significance if free T4 is normal 3

5. Non-Thyroidal Illness (Sick Euthyroid Syndrome)

   • Intercurrent illness affecting thyroid hormone levels 4
   • Medication effects (amiodarone, heparin, etc.) 4

Diagnostic Approach

1. Initial Testing

   • Comprehensive thyroid function testing including TSH, Free T4, and thyroid peroxidase antibodies 1
   • If TSH is normal and T4 is low, suspect central hypothyroidism 5

2. Additional Testing for Suspected Central Hypothyroidism

   • Evaluate for other pituitary hormone deficiencies 1
   • Check for adrenal insufficiency before starting thyroid hormone treatment 1
   • Consider pituitary imaging (MRI) to identify tumors or structural abnormalities

3. Rule Out Laboratory Interference

   • Repeat testing in different laboratory 3
   • Consider dilution studies if heterophile antibody interference is suspected 3
   • Measure TBG levels if low total T4 but normal free T4 3

Treatment Approach

1. For Central Hypothyroidism

   • Critical Step: Check for concurrent adrenal insufficiency before starting thyroid hormone 1
   • If both adrenal insufficiency and hypothyroidism are present, always start steroid replacement first 1
   • Levothyroxine replacement therapy guided by free T4 levels, not TSH 1, 6
   • Dosing recommendations:
     • Patients under 70 without cardiac disease: 1.6 mcg/kg/day 1
     • Elderly patients or those with cardiac conditions: 25-50 mcg/day 1
     • Target free T4 in upper half of reference range 1, 6

2. For Iodine Deficiency

   • Iodine supplementation to correct deficiency 2
   • Monitor for normalization of thyroid hormone levels

3. Monitoring Treatment

   • In central hypothyroidism, monitor free T4 and free T3 levels, not TSH 6, 5
   • Recheck thyroid function 4-6 weeks after initiating or adjusting levothyroxine 1
   • Once stable, monitor every 6-12 months 1

Important Pitfalls to Avoid

1. Misdiagnosis

   • Don't rely solely on TSH for diagnosis or monitoring in central hypothyroidism 1, 6, 5
   • Avoid misinterpreting laboratory interference as thyroid disease 3, 4

2. Treatment Errors

   • Never start thyroid hormone before treating adrenal insufficiency (can precipitate adrenal crisis) 1
   • Avoid overtreatment with excessive thyroid hormone (increases risk of atrial fibrillation and osteoporosis) 1

3. Monitoring Challenges

   • In central hypothyroidism, TSH suppression is expected and appropriate 1
   • Both free T4 and free T3 should be monitored to identify over- or under-treatment 6
   • Consider biochemical indexes of thyroid hormone action for more accurate assessment 6

By systematically evaluating the causes of low T4 with normal TSH and following appropriate treatment guidelines, patients can achieve optimal thyroid hormone replacement and avoid complications associated with under- or over-treatment.