Thyroid Function Tests (TFTs)

University Exam Answer - 10 Marks (ENT / Surgery Pattern)

Introduction

1. Tests measuring thyroid hormones
2. Tests measuring TSH (pituitary-thyroid axis)
3. Tests of thyroid autoimmunity
4. Functional/imaging tests

1. Serum Thyroid-Stimulating Hormone (TSH)

• This is the single most sensitive and specific test for diagnosing hyper- and hypothyroidism, and is the recommended first-line screening test.
• The assay is immunometric: monoclonal TSH antibodies bound to a solid matrix capture serum TSH, and a second labeled antibody binds a separate epitope - the signal is proportional to TSH concentration.
• There is an inverse logarithmic relationship between free T4 and TSH - small changes in free T4 cause large shifts in TSH levels.
• TSH is elevated in primary hypothyroidism and suppressed in hyperthyroidism.
• The ultrasensitive (third-generation) TSH assay is now standard and can detect levels as low as 0.01 μIU/mL.
• TSH is the only test necessary in most clinically euthyroid patients with thyroid nodules.

2. Total Thyroxine (Total T4) and Total Triiodothyronine (Total T3)

• Measured by radioimmunoassay (RIA) - reflects both free + protein-bound fractions.
• Total T4 reflects thyroid gland output; total T3 reflects peripheral hormone metabolism.
• Limitations: Total T4 is elevated in states of increased thyroid-binding globulin (TBG) - pregnancy, estrogen/OCP use, congenital TBG excess - even in euthyroid individuals. Conversely, total T4 falls with decreased TBG (anabolic steroids, nephrotic syndrome) even if free T4 is normal.
• Total T3 measurement is important when clinical hyperthyroidism is present with normal T4 - this is T3 thyrotoxicosis.
• Total T3 is often elevated in early hypothyroidism (compensatory peripheral conversion).

3. Free T4 (FT4) and Free T3 (FT3)

• Measured by RIA; represent the biologically active fraction unbound to carrier proteins.
• Free T4 is more accurate than total T4 as it is not affected by TBG levels.
• Free T4 is used in cases of early hyperthyroidism where total T4 may be normal.
• In Refetoff's syndrome (end-organ resistance to T4), T4 levels are elevated but TSH is paradoxically normal.
• Free T3 is the most useful test to confirm early hyperthyroidism - both free T4 and free T3 rise before total T4 and total T3.
• Free T4 can also be estimated indirectly by the T3 resin uptake (T3RU) test: if free T4 is high, fewer hormone-binding sites are available for radiolabeled T3, so more T3 binds the ion-exchange resin → elevated T3RU.

4. TRH Stimulation Test

• 500 μg TRH is administered IV; TSH is measured at 0, 30, and 60 minutes.
• Normal response: TSH rises ≥6 μIU/mL above baseline.
• Useful to evaluate pituitary TSH secretory reserve.
• Formerly used to assess borderline hyperthyroidism, but now largely replaced by sensitive TSH assays.
• In hyperthyroidism: TSH shows a blunted/flat response to TRH.
• In hypothyroidism: Exaggerated TSH response (primary) or absent response (pituitary/secondary hypothyroidism).

5. Thyroid Autoantibodies

• Normal: TSI <140% of baseline; Anti-TPO ≤100 WHO units; Anti-Tg <200 IU/mL
• These antibodies do not measure thyroid function - they indicate the underlying autoimmune disorder.
• Anti-Tg antibodies can interfere with serum thyroglobulin assays and must always be co-measured.

6. Serum Thyroglobulin (Tg)

• Thyroglobulin is produced only by thyroid tissue (normal or malignant).
• Normal values: Women 1.5-38.5 mcg/L; Men 1.4-29.2 mcg/L.
• Elevated in: thyroiditis, Graves' disease, toxic multinodular goiter.
• Most important clinical use: Monitoring for recurrence of differentiated thyroid cancer (papillary/follicular) after total thyroidectomy + radioiodine ablation. An undetectable Tg level post-ablation indicates remission; any rise suggests recurrence.

7. Radioiodine Uptake (RAIU) Test

• Normal: 5-35% uptake at 24 hours (¹²³I or ¹³¹I).
• Increased uptake: Hyperthyroidism (Graves', toxic MNG, toxic adenoma).
• Decreased uptake: Hypothyroidism, thyroiditis (subacute/Hashimoto's), factitious thyrotoxicosis, iodine excess.
• ⁹⁹ᵐTc pertechnetate: taken up but not organified; shorter half-life; increasingly used for thyroid scintigraphy.
• "Cold" nodules (decreased uptake) carry a 20% malignancy risk vs. <5% for hot/warm nodules.

8. Serum Calcitonin

• Normal: 0-4 pg/mL (basal); produced by parafollicular C cells.
• Elevated in medullary thyroid carcinoma (MTC); used as tumor marker and for post-operative surveillance.
• Mild hypercalcemia is seen in 15-20% of thyrotoxicosis patients.

Summary Table: TFTs in Clinical Conditions

Approach to TFT Interpretation

1. Start with TSH - the best screening test.
2. If TSH is abnormal, add Free T4 (and Free T3 if TSH low but T4 normal).
3. Add antibodies if autoimmune disease is suspected.
4. Add thyroglobulin for thyroid cancer follow-up.
5. Add RAIU/scan to characterize function and morphology.
6. TRH stimulation test if pituitary-thyroid axis assessment is needed.

• Schwartz's Principles of Surgery, 11th Ed., Evaluation of Patients With Thyroid Disease
• Katzung's Basic and Clinical Pharmacology, 16th Ed., Evaluation of Thyroid Function (Table 38-2)
• Harper's Illustrated Biochemistry, 32nd Ed., Thyroid Function Tests