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Thyroid Function Tests (TFT) - Complete Notes

1. The Hypothalamic-Pituitary-Thyroid (HPT) Axis - Understanding the Foundation

Hypothalamus → TRH (Thyrotropin-Releasing Hormone)
      ↓
Pituitary → TSH (Thyroid-Stimulating Hormone)
      ↓
Thyroid gland → T4 (Thyroxine) + T3 (Triiodothyronine)
      ↓
Negative feedback back to hypothalamus + pituitary

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2. The Tests - What They Measure and Why

A. TSH (Thyroid-Stimulating Hormone)

• Normal range: ~0.5-4.5 mIU/L (lower in early pregnancy: ~0.1-4.0 mIU/L)
• Made by the anterior pituitary
• Third-generation ultrasensitive assay can detect levels as low as 0.01 mU/L - this is the gold standard test
• Because of the log-linear inverse relationship, TSH rises early even when T4 is still within normal range - it is the single most sensitive screening test for primary thyroid dysfunction
• A normal TSH essentially excludes thyroid dysfunction in most patients - no further testing needed
• Schwartz's Surgery - the ultrasensitive TSH assay is the most sensitive and specific test for both hyper- and hypothyroidism

B. Total T4

• Normal range: 55-150 nmol/L
• Measures both free and protein-bound T4 (>99% is bound - mostly to TBG, some to albumin and transthyretin)
• Problems: affected by anything that changes TBG levels (pregnancy, estrogens, androgens, liver disease, nephrotic syndrome) - these change total T4 without changing actual thyroid function
• Not used as first-line test for this reason

C. Free T4 (fT4)

• Normal range: 12-28 pmol/L
• Measures only the biologically active unbound fraction
• Reliable in most settings; used when TSH is abnormal to confirm and grade dysfunction
• Use: confirms overt hypo/hyperthyroidism, rules out TBG interference

D. Total T3

• Normal range: 1.5-3.5 nmol/L
• Reflects mainly peripheral conversion of T4 → T3 (not thyroid output directly)
• Not suitable as a general screening test
• Key use: T3 toxicosis - about 5% of hyperthyroid patients have normal T4 but elevated T3 (Graves disease/toxic nodular goiter preferentially secrete T3)
• In early hypothyroidism, T3 levels are often preserved or even elevated (body compensates by increasing T4→T3 conversion)

E. Free T3 (fT3)

• Normal range: 3-9 pmol/L
• Most useful to confirm early hyperthyroidism (free T4 and free T3 rise before total T4/T3)
• Difficult to measure accurately at low levels - total T3 often used instead in practice

F. T3 Resin Uptake (T3RU) - Indirect Test

• An older indirect measure of TBG saturation
• If free T4 is high: fewer TBG binding sites are available for radiolabeled T3 → more T3 binds the resin → T3RU is HIGH
• Useful to calculate Free T4 Index (FT4I = Total T4 × T3RU) when direct fT4 assays aren't available

G. TRH Stimulation Test

• Administer 500 mcg TRH IV; measure TSH at 30 and 60 minutes
• Normal response: TSH rises by at least 6 μIU/mL from baseline
• Use: largely replaced by sensitive TSH assays; still used occasionally to confirm pituitary hypothyroidism (central hypothyroidism)
• Inappropriate TSH response to TRH = pituitary hypothyroidism confirmed

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3. The "TSH-First" Algorithm - Clinical Approach

Step 1: Measure TSH
│
├─ TSH NORMAL → Thyroid dysfunction essentially excluded (stop)
│
├─ TSH HIGH → Add free T4
│     ├─ High TSH + Low fT4 = OVERT HYPOTHYROIDISM
│     └─ High TSH + Normal fT4 = SUBCLINICAL HYPOTHYROIDISM
│
└─ TSH LOW → Add free T4 AND free/total T3
      ├─ Low TSH + High fT4/T3 = OVERT HYPERTHYROIDISM
      ├─ Low TSH + Normal fT4 → Check free T3
      │     ├─ High T3 = T3 TOXICOSIS
      │     └─ Normal T3 = SUBCLINICAL HYPERTHYROIDISM
      └─ Very low/undetectable TSH alone = significant thyrotoxicosis

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4. Interpretation Summary Table

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5. Thyroid Antibodies

• Anti-TPO + Anti-Tg do NOT tell you thyroid function - they indicate the underlying disorder
• ~80% of Hashimoto patients have elevated antibody levels
• TRAb are highly sensitive AND specific for Graves disease

Serum Thyroglobulin (Tg)

• Only made by normal or abnormal thyroid tissue
• Main clinical use: tumor marker for differentiated thyroid cancer surveillance after total thyroidectomy + RAI ablation
• Always check anti-Tg antibodies alongside Tg (they interfere with the assay)

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6. When to Abandon the "TSH-First" Rule

• Cytokines from systemic illness suppress the HPT axis
• Pattern: ↓T3, ↓T4, ↑reverse T3 (rT3), normal or low TSH
• Patient is actually euthyroid - the tests are abnormal, not the thyroid
• Rule: Do NOT routinely check TFTs in critically ill patients unless there is strong clinical suspicion of pre-existing thyroid disease

• After treating hyperthyroidism: TSH may remain suppressed for months (prolonged thyrotroph cell suppression)
• After starting levothyroxine: TSH may remain elevated for weeks (thyrotroph hyperplasia)
• Wait at least 6-8 weeks after a dose change before rechecking TSH (steady state reached ~end of 2nd month in compliant patients)

• TSH will be inappropriately low or normal despite low T4
• Must interpret TSH and fT4 together - TSH alone will miss central hypothyroidism
• Clue: TSH is rarely the only pituitary hormone deficient - check all pituitary axes

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7. Drugs and TFTs - Clinically Vital

Drugs that Cause TRUE Thyroid Dysfunction

Drugs that Alter TESTS Without Affecting True Function

Clinical tip: In patients on estrogens or OCPs - total T4/T3 will be high, but free T4 and TSH are normal. Patient is euthyroid. No intervention needed.

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8. Specific Clinical Scenarios

Graves Disease

• Autoantibody (TRAb/TSI) acts as a TSH agonist → continuous unregulated stimulation
• TFT: Low/undetectable TSH, high fT4, high T3 (T3:T4 ratio >20:1 suggests Graves or toxic nodule over thyroiditis)
• Confirm: TRAb titer highly sensitive + specific
• Also has: exophthalmos, pretibial myxedema (not from TFT but clinical features)

Hashimoto Thyroiditis

• Most common cause of hypothyroidism in developed countries
• TFT: elevated TSH, low/normal fT4
• Antibodies: anti-TPO + anti-Tg elevated
• Note: TSI (TRAb) is NOT found in Hashimoto - this distinguishes it from Graves

Subacute (De Quervain) Thyroiditis

• Painful thyroid, elevated ESR, often follows viral illness
• Releases stored hormones → transient hyperthyroidism → then hypothyroidism → recovery
• T3:T4 ratio lower than Graves (reflects ratio of stored hormones)
• ESR elevated - useful diagnostic clue

Monitoring Thyroid Cancer

• After total thyroidectomy + RAI ablation: use serum Tg as tumor marker
• Always check anti-Tg antibodies simultaneously (they interfere with Tg assay)
• TSH stimulation (by stopping levothyroxine or using recombinant TSH) enhances Tg sensitivity for detecting recurrence

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9. Special Populations

Pregnancy

• Normal TSH range is lower in pregnancy (~0.1-4.0 mIU/L in 1st trimester)
• hCG cross-reacts with TSH receptors → slight T4 elevation + TSH suppression in 1st trimester (physiologic)
• ↑ TBG from estrogen → ↑ Total T4, but free T4 remains normal
• Hypothyroid women on levothyroxine often need 25-50% dose increase in pregnancy

Neonatal Screening (Congenital Hypothyroidism)

• Screened at 48-72 hours of age; some advocate a second screen at 2-6 weeks
• Approaches vary: primary TSH, primary T4 with backup TSH, or both simultaneously
• TSH-only approach misses: central hypothyroidism + delayed TSH rise cases
• Most common cause: abnormal thyroid gland development (agenesis/dysgenesis)
• Untreated: irreversible intellectual and growth retardation (cretinism)

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10. Quick Reference - Clinical Pearls

1. TSH is always first - most sensitive test, amplifies small T4 changes
2. Normal TSH = normal thyroid function (in most patients, most settings)
3. Add fT4 when TSH is abnormal to confirm and grade severity
4. Add T3 when TSH is low but fT4 is normal - look for T3 toxicosis
5. In central disease - TSH and fT4 must be read together, not TSH alone
6. In critical illness - euthyroid sick syndrome mimics central hypothyroidism; avoid TFTs unless strong suspicion
7. After dose changes - wait 6-8 weeks before rechecking (TSH lags)
8. Amiodarone does everything to TFTs - inhibits T4→T3 conversion (↑T4, ↓T3 even in euthyroid patients) + can cause either hypo or hyperthyroidism
9. Biotin supplements interfere with assays - hold 1-2 days before testing
10. Estrogens raise total T4/T3 but not free T4 or TSH - no treatment needed

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• HPT Axis diagram - the feedback loop visualised as a table with the key log-linear concept highlighted in amber
• The Tests table - TSH, fT4, Total T4, fT3, Total T3, TRH Stim test with normal ranges and clinical notes
• TSH-First Algorithm flowchart - colour-coded branching from normal/high/low TSH to all diagnoses (overt hypo, subclinical hypo, overt hyper, subclinical hyper, T3 toxicosis)
• Interpretation Summary Table - 11 conditions with colour-coded TSH/fT4/T3 arrows (red = elevated, green = decreased)

• Thyroid Antibodies table - Anti-TPO, Anti-Tg, TRAb/TSI, Thyroglobulin, Calcitonin with disease associations
• When TSH-First Fails - red alert section covering euthyroid sick syndrome, therapy transitions, and central disease
• Drugs & TFTs (two-column) - left column = true dysfunction (amiodarone, lithium, iodine, checkpoint inhibitors), right column = test artifact only (estrogens, phenytoin, heparin, biotin warning)
• 10 Clinical Pearls - teal-highlighted numbered list with the most clinically actionable points
• Source footnote from authoritative textbooks