How to manage a patient with hypothyroidism (low T4) and normal Thyroid-Stimulating Hormone (TSH) levels?

Management of Low T4 with Normal TSH

Patients with low T4 and normal TSH should be evaluated for central hypothyroidism (secondary or tertiary) which requires thyroid hormone replacement therapy targeting free T4 levels in the upper half of the normal range rather than TSH normalization. 1

Diagnostic Approach

When encountering a patient with low T4 and normal TSH, consider:

1. Confirm the abnormality

   • Repeat thyroid function tests (TSH and free T4) within 2-3 months to ensure accuracy 1
   • Morning testing (around 8 am) is preferred for accurate assessment 2

2. Evaluate for central hypothyroidism

   • Central hypothyroidism is characterized by low/normal TSH with low free T4 2
   • Consider additional pituitary hormone testing:
     • ACTH and cortisol (or 1 mcg cosyntropin stimulation test)
     • Gonadal hormones (testosterone in men, estradiol in women)
     • FSH and LH 2

3. Imaging

   • MRI of the sella with pituitary cuts to evaluate for pituitary abnormalities 2
   • Look for stalk thickening, suprasellar convexity, or pituitary enlargement 2

Treatment Algorithm

1. For confirmed central hypothyroidism:

   • Initiate levothyroxine therapy 1, 3
   • Important: If both adrenal insufficiency and hypothyroidism are present, always start steroids BEFORE thyroid hormone to avoid adrenal crisis 2

2. Dosing considerations:

   • For most adults: Start with 1.6 mcg/kg/day based on ideal body weight 1, 3
   • For elderly patients or those with cardiac conditions: Start lower at 25-50 mcg/day 1
   • Administer as a single daily dose on an empty stomach, 30-60 minutes before breakfast 3

3. Monitoring and titration:

   • Unlike primary hypothyroidism, do NOT use TSH to guide therapy 1, 3
   • Instead, monitor free T4 levels, targeting the upper half of the normal range 1, 3
   • Check free T4 every 6-8 weeks during dose adjustment 1
   • Once stable, monitor annually or sooner if clinical status changes 1

Special Considerations

1. Pituitary hypophysitis

   • Common cause of central hypothyroidism, especially in patients on immune checkpoint inhibitors (particularly anti-CTLA-4 antibodies like ipilimumab) 2
   • May present with headache (85%) and fatigue (66%) 2
   • Often requires lifelong hormone replacement 2

2. Medication timing

   • Taking levothyroxine before breakfast is more effective than before dinner
   • Changing administration time from before breakfast to before dinner can result in increased TSH levels and decreased therapeutic efficacy 4
   • Avoid taking with calcium, iron supplements, or medications that impair absorption 1

3. Other causes of low T4 with normal TSH

   • Resistance to thyroid hormone alpha (genetic THRA variants) 5
   • Non-thyroidal illness syndrome (sick euthyroid syndrome) in acutely ill patients 6
   • Assay interference 7

Pitfalls and Caveats

1. Avoid misdiagnosis

   • Low T4 with normal TSH occurs in approximately 3.3% of thyroid function tests 7
   • Thorough investigation is needed to identify the underlying cause 7

2. Avoid undertreatment

   • In central hypothyroidism, TSH cannot be used to monitor therapy adequacy 1, 3
   • Persistent low free T4 despite treatment can lead to hypothyroid symptoms and complications 1

3. Avoid overtreatment

   • Excessive levothyroxine can cause iatrogenic hyperthyroidism 1
   • This may lead to decreased bone mineral density, increased fracture risk, and cardiac arrhythmias, especially in older adults 1

4. Medical alert

   • All patients with adrenal insufficiency should obtain and carry a medical alert bracelet 2

By following this structured approach, central hypothyroidism can be properly diagnosed and treated, optimizing patient outcomes and quality of life.