What is the workup for a patient with normal Thyroid-Stimulating Hormone (TSH) and low free Thyroxine (T4)?

Workup for Normal TSH and Low Free T4

The most critical first step is to determine whether this represents central (secondary) hypothyroidism, assay interference, or a binding protein abnormality—measure additional pituitary hormones (morning cortisol, ACTH, FSH, LH, prolactin) and obtain pituitary MRI imaging to evaluate for pituitary or hypothalamic dysfunction. 1

Initial Diagnostic Considerations

This pattern of normal TSH with low free T4 is uncommon and requires systematic evaluation of three main possibilities:

1. Central Hypothyroidism (Most Important to Rule Out)

Central hypothyroidism occurs when pituitary or hypothalamic dysfunction prevents appropriate TSH elevation despite low thyroid hormone levels. 1 This is the most clinically significant diagnosis to exclude, as it:

• Requires evaluation for other pituitary hormone deficiencies (ACTH deficiency can be life-threatening) 1
• Necessitates different treatment monitoring (free T4 levels, not TSH) 1
• May indicate structural pituitary pathology requiring imaging 1

Order the following tests immediately:

• Morning cortisol and ACTH (to assess for adrenal insufficiency) 1
• FSH, LH, and sex hormones (testosterone in men, estradiol in women) 1
• Prolactin 1
• Pituitary MRI if not previously performed 1

2. Assay Interference or Binding Protein Abnormalities

Laboratory interference from heterophile antibodies or thyroxine-binding globulin (TBG) deficiency can produce discordant results between TSH and free T4. 2

Evaluate for interference by:

• Measuring total T4 and T3 (if low with normal TSH, suggests TBG deficiency) 2
• Measuring TBG levels directly 2
• Requesting the laboratory perform serial dilution studies if interference is suspected 3, 2
• Repeating tests in a different laboratory using alternative assay methods 2

TBG deficiency is a hereditary condition with no clinical significance—patients are biochemically but not clinically hypothyroid. 2 If total T4 and T3 are low but TSH is normal and TBG is low, this confirms the diagnosis and no treatment is needed. 2

3. Transient TSH Suppression from Prior Hyperthyroidism

In patients recently treated for hyperthyroidism, TSH can remain suppressed for weeks to months even after developing iatrogenic hypothyroidism from excessive antithyroid medication. 3

• Review medication history for recent methimazole, propylthiouracil, or radioactive iodine treatment 3
• If present, this represents true hypothyroidism requiring levothyroxine, but TSH will normalize slowly 3

Diagnostic Algorithm

Step 1: Confirm the low free T4 result by repeating in 3-6 weeks, as 30-60% of abnormal thyroid tests normalize spontaneously 4

Step 2: Simultaneously measure:

• TSH (repeat)
• Free T4 (repeat)
• Total T4 and T3
• TBG
• Morning cortisol and ACTH
• FSH, LH, sex hormones
• Prolactin 1, 2

Step 3: Interpret results:

• If total T4/T3 are also low with normal TSH and low TBG: Diagnosis is TBG deficiency—no treatment needed 2

• If free T4 remains low, TSH normal/low, and other pituitary hormones are abnormal: Diagnosis is central hypothyroidism—obtain pituitary MRI and refer to endocrinology 1

• If repeat testing shows normalized free T4: Likely laboratory error or transient variation—no further workup needed 4

• If heterophile antibody interference suspected (discordant results across multiple tests): Request serial dilution studies and alternative assay methods 3, 2

Critical Management Points if Central Hypothyroidism is Confirmed

Never start levothyroxine before ruling out adrenal insufficiency, as this can precipitate life-threatening adrenal crisis. 4, 1 If cortisol is low, start hydrocortisone replacement first, then begin levothyroxine after 1-2 weeks. 4

For central hypothyroidism, titrate levothyroxine based on free T4 levels (target upper half of normal range), NOT TSH, as TSH is unreliable in this condition. 1 Start with 1.6 mcg/kg/day in younger patients without cardiac disease, or 25-50 mcg daily in elderly or cardiac patients. 1

Monitor free T4 every 6-8 weeks during dose titration, then every 6-12 months once stable. 1

Common Pitfalls to Avoid

• Failing to recognize central hypothyroidism and treating based on "normal" TSH alone—this misses a potentially serious pituitary disorder 1
• Starting thyroid hormone without evaluating for adrenal insufficiency in suspected central hypothyroidism—this can be fatal 4, 1
• Accepting discordant laboratory results at face value without considering assay interference or binding protein abnormalities 2
• Treating TBG deficiency with levothyroxine—this is a benign hereditary condition requiring no intervention 2