Thyriod function test

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thyroid function tests TSH T3 T4 interpretation clinical guide

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Thyroid Function Tests (TFTs)

Overview

Thyroid function tests assess the hormonal output of the thyroid gland and the pituitary-thyroid feedback axis. The main tests are TSH, Free T4 (fT4), Free T3 (fT3), Total T4, Total T3, and sometimes Reverse T3 (rT3).

The Thyroid Axis - How It Works

The hypothalamus releases TRH (Thyrotropin-Releasing Hormone) → stimulates the pituitary to release TSH (Thyroid-Stimulating Hormone) → TSH stimulates the thyroid gland to produce and secrete:

T4 (Thyroxine) - a prohormone; the major secretory product
T3 (Triiodothyronine) - the active hormone

Circulating T4 is slowly metabolized - mostly converted to the active T3, with a smaller fraction converted to the inactive reverse T3 (rT3). T3 and T4 then feed back to suppress further TRH and TSH release.

Small changes in free T3 and T4 produce large changes in serum TSH - this amplification makes TSH a very sensitive marker. - Quick Compendium of Clinical Pathology, 5th ed.

Individual Tests

1. TSH (Thyroid-Stimulating Hormone / Thyrotropin)

Parameter	Details
Normal range	~0.4 - 4.0 mIU/L (lab-dependent)
Best use	First-line screening for thyroid dysfunction
Key principle	Inversely reflects thyroid hormone levels

TSH is the single best test for initially assessing thyroid function - a normal TSH essentially excludes primary thyroid dysfunction and no further testing is usually needed.
TSH rises in hypothyroidism (pituitary compensates) and falls in hyperthyroidism.
Quick Compendium of Clinical Pathology, 5th ed.

2. Free T4 (fT4)

Only ~0.02% of total T4 circulates unbound (free); the rest is bound to TBG (Thyroxine-Binding Globulin) and prealbumin (transthyretin).
Free T4 is the biologically relevant fraction and is not affected by TBG level changes.
Measured if TSH is abnormal; elevated in hyperthyroidism, low in hypothyroidism.
Free T4 by equilibrium dialysis is the most accurate method but is slow; immunoassay is standard.

3. Free T3 (fT3)

Only ~0.2% of total T3 is free; also TBG-independent.
Less commonly measured than fT4, but used when:
- TSH is suppressed but fT4 is normal (to diagnose T3 toxicosis)
- Monitoring patients on oral T3 therapy
- Investigating interference with fT4 assay
- Diagnosing secondary hypothyroidism
Quick Compendium of Clinical Pathology, 5th ed.

4. Total T4 and Total T3

Include both bound and free hormone; affected by TBG levels.
TBG is increased by: pregnancy, oral contraceptives, estrogen therapy, active hepatitis, hypothyroidism → falsely elevated total T4/T3.
TBG is decreased by: hypoproteinemic states, androgen therapy, cortisol → falsely low total T4/T3.
Less useful than free hormone measurements; free T4 and fT3 correlate better with clinical status.

5. Reverse T3 (rT3)

An inactive metabolite of T4 conversion.
Elevated in euthyroid sick syndrome (non-thyroidal illness).
Normal in primary hypo/hyperthyroidism.

6. T3 Resin Uptake (T3RU) - Now Largely Obsolete

A historical indirect measure of TBG binding capacity:

Radiolabeled T3 added to serum; any excess binds to added resin.
Low T3RU = more TBG binding sites available = hypothyroidism (or high TBG).
High T3RU = fewer TBG sites = hyperthyroidism (or low TBG).
The Free Thyroxine Index (FTI) = T3RU × total T4; largely replaced by direct free T4 measurement.

7. RAIU (Radioactive Iodine Uptake) - Nuclear Medicine Test

Patient given radioactive iodine; thyroid scanned for uptake:

Increased RAIU - Graves disease, functioning autonomic adenoma.
Decreased RAIU - thyroiditis, struma ovarii, exogenous thyroid hormone use.

TFT Interpretation Patterns

Condition	TSH	Free T4	Free T3	rT3
Primary hyperthyroidism	↓	↑	↑	→
Primary hypothyroidism	↑	↓	↓	→/↓
Euthyroid sick syndrome	→ (or ↓)	→/↓	↓	↑
T3 toxicosis	↓	→	↑	→
Secondary (central) hypothyroidism	→/↓	↓	↓	-
Subclinical hypothyroidism	↑	→	→	-
Subclinical hyperthyroidism	↓	→	→	-

- Quick Compendium of Clinical Pathology, 5th ed.

Clinical Approach: TSH-First Strategy

Step 1: Measure TSH.

If normal → thyroid dysfunction effectively excluded in most patients; no further testing needed.
If abnormal → proceed to Free T4.

Step 2: Measure Free T4 (if TSH is abnormal).

If TSH low + fT4 high → hyperthyroidism.
If TSH high + fT4 low → hypothyroidism.
If TSH low + fT4 normal → measure Free T3 (suspect T3 toxicosis).

Step 3: Free T3 measured in select circumstances (as above).

When TSH-First Policy Should Be Abandoned

Critically ill patients - euthyroid sick syndrome causes low T3, low/normal T4, and low/normal TSH without true thyroid disease. TFTs should NOT be routinely ordered in the ICU unless strong clinical suspicion exists.
Early thyroid therapy - TSH may remain abnormally low for months after treating hyperthyroidism (pituitary thyrotroph suppression), or take weeks to normalize after starting levothyroxine. Steady state achieved by ~2 months.
Suspected pituitary or hypothalamic disease (central hypothyroidism) - TSH may be normal or low despite low T4; diagnosis requires combined TSH + fT4 interpretation.
- Washington Manual of Medical Therapeutics

Effect of Drugs on TFTs

Effect	Drug
↓ fT4 + ↑ TSH (true hypothyroidism)	Iodine (amiodarone, contrast media), lithium, tyrosine kinase inhibitors, interferon-α, checkpoint inhibitors
↓ TSH (suppress secretion)	Glucocorticoids, dopamine
Multiple mechanisms, TSH normal	Phenytoin
↓ Total T4 only (↓ TBG)	Androgens
Inhibit T4 binding to TBG	High-dose furosemide, salicylates
↑ fT4 + ↓ TSH (true hyperthyroidism)	Iodine (amiodarone), some immune modulators

- Washington Manual of Medical Therapeutics

Euthyroid Sick Syndrome (Non-Thyroidal Illness, NTI)

Many illnesses alter TFTs WITHOUT causing true thyroid dysfunction. Key patterns:

Low T3: Most common change. Decreased T4 to T3 conversion. Seen in starvation, surgery, trauma, and systemic illness. TSH and fT4 are normal. No treatment needed.
Low T4: In severe illness. TSH initially decreases (sometimes to <0.1 μU/mL). During recovery, TSH may transiently rise (rarely >20 μU/mL).
Increased rT3 is characteristically elevated.

Summary Table: Test Selection

Clinical Question	Best Test
Screen for thyroid dysfunction	TSH
Confirm hypo/hyperthyroidism	TSH + Free T4
Suspect T3 toxicosis	TSH + Free T3
Monitor levothyroxine therapy	TSH (after steady state ~2 months)
Suspect central hypothyroidism	TSH + Free T4 combined
TBG abnormality suspected	Free T4/T3 (not total)
Differentiate thyroiditis from Graves	RAIU

Key Teaching Points:

TSH is the most sensitive and specific single test for thyroid function - use it first.
Only ~0.02% of T4 is free; binding protein changes (pregnancy, OCP, illness) significantly alter total T4 without reflecting true thyroid status.
Always interpret TFTs in clinical context - several drug effects and NTI mimic true thyroid disease.
In central (pituitary) disease, TSH can be inappropriately normal or low despite true hypothyroidism.

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