Thyroid hormone levels

Why TSH first

TSH is the single most useful test of thyroid function
- Log-linear relationship to free T4 - a small fT4 change produces a large TSH change
- Only valid when the pituitary-thyroid axis is intact and steady - not in pituitary disease, not in acute illness, not within 6-8 weeks of a dose change

Test	Use
TSH	First line, screening, monitoring primary disease
Free T4	Add when TSH abnormal, or when TSH cannot be trusted (pituitary disease, amiodarone, recent treatment)
Free T3	T3-toxicosis, amiodarone, assessing severity of thyrotoxicosis. Not useful in hypothyroidism
TPO Ab	Autoimmune thyroiditis; predicts progression of subclinical hypothyroidism
TRAb	Graves' - diagnosis, pregnancy risk stratification, relapse prediction
Thyroglobulin	Post-thyroidectomy DTC surveillance; factitious thyrotoxicosis

TFTs are among the most frequently requested pathology tests, and among the most frequently misinterpreted
~5-10% of adults have subclinical thyroid dysfunction
Around 1 in 20 hospitalised patients has an abnormal TFT from non-thyroidal illness alone

Iodide trapped by NIS -> organified by thyroid peroxidase (TPO) onto tyrosyl residues of thyroglobulin (a large ~660 kDa glycoprotein, ~120 tyrosines) -> MIT + DIT couple -> T4 and T3 -> stored in colloid -> proteolysed on TSH stimulation
T4 is secreted exclusively by the thyroid
~80% of circulating T3 is generated peripherally by 5'-deiodination of T4
- T3 is the active hormone (~10x receptor affinity)

	T4	T3
Half-life	~6.7 days	~0.75 days
Source	Thyroid only	~20% thyroid, ~80% peripheral conversion
Protein bound	~99.97% (~70% to TBG)	~99.7%

The long T4 half-life is why levothyroxine is dosed once daily, why a missed dose does not matter, and why TFTs are rechecked at 6-8 weeks not 2

D1 (liver, kidney, thyroid) - T4 -> T3
D2 (brain, pituitary, muscle, BAT) - local intracellular T3; sets pituitary TSH feedback
D3 - inactivating: T4 -> reverse T3, T3 -> T2

TBG (~70%), transthyretin, albumin
Total T4/T3 track the binding protein; free hormone is what matters
- inc TBG: pregnancy, oestrogen/OCP, tamoxifen, hepatitis, heroin, congenital
- dec TBG: androgens, glucocorticoids, nephrotic syndrome, cirrhosis, severe illness, congenital
- Displacement from binding: furosemide, heparin, salicylates, phenytoin, carbamazepine, NSAIDs

TSH	fT4	Interpretation
inc	dec	Primary hypothyroidism
inc	normal	Subclinical hypothyroidism
dec	inc	Primary thyrotoxicosis
dec	normal (check fT3)	Subclinical hyperthyroidism, or T3-toxicosis if fT3 inc
dec/normal	dec	Central (secondary) hypothyroidism - TSH is NOT low enough to be reassuring; check the rest of the pituitary
normal/inc	inc	TSH-oma, thyroid hormone resistance, assay interference, heparin artefact, amiodarone, non-compliance with recent big dose
dec	dec (low fT3, inc rT3)	Non-thyroidal illness

Sequence: dec T3 first (D3 activation) -> then dec TSH -> then dec T4 in severe illness -> rebound inc TSH in recovery
*Do not test thyroid function in acute illness unless thyroid disease is genuinely suspected*
Low T4 + low TSH in ICU = poor prognosis marker, not treatable hypothyroidism

Biotin (high-dose supplements, MS trials) - biotin-streptavidin immunoassays -> falsely low TSH with falsely high fT4/fT3, and false-positive TRAb mimicking Graves'
- Stop biotin 48-72 h and repeat
Heparin / LMWH - in-vitro lipase release -> NEFA displace T4 -> spuriously high fT4/fT3 with normal TSH, mimicking a TSH-oma
Heterophile / anti-mouse antibodies, macro-TSH -> falsely high TSH
Anti-T4/T3 autoantibodies
Discordant result -> repeat on a different platform before investigating a pituitary tumour

Rises with: high TSH, Graves'/autoimmune thyroid disease, thyroiditis, neonatal period, thyroid cancer, goitre
Undetectable in factitious thyrotoxicosis (exogenous T4) and in athyreosis - useful in the congenital hypothyroidism workup
*Anti-thyroglobulin antibody falsely lowers Tg* - must be measured with every Tg in cancer surveillance; the antibody trend then becomes the tumour marker

Amiodarone - transient inc TSH early (D1 inhibition), then AIT type 1 (iodine-induced) or type 2 (destructive)
Lithium - hypothyroidism, goitre
Checkpoint inhibitors - thyroiditis then hypothyroidism
TKIs (sunitinib) - hypothyroidism
Oral oestrogen raises T4 requirement; PPIs, calcium, iron, soy, coffee reduce levothyroxine absorption

Recheck TFTs 6-8 weeks after any levothyroxine dose change - shorter is uninterpretable
Take the blood sample before the morning levothyroxine dose (fT4 peaks 2-4 h post-dose)
Levothyroxine on an empty stomach, 30-60 min before food, separated by 4 h from calcium, iron, PPIs

Central hypothyroidism -> titrate to fT4 in the upper half of the reference range
Pregnancy -> trimester-specific reference ranges; requirement rises ~25-50% in the first trimester
Recently treated thyrotoxicosis -> TSH stays suppressed for weeks to months; use fT4/fT3
Amiodarone, dopamine, high-dose glucocorticoids, severe illness -> TSH suppressed independently of thyroid status

No case-finding in asymptomatic adults
Test: AF, unexplained weight change, dyslipidaemia, hyponatraemia, infertility/menstrual disturbance, dementia, T1DM and other autoimmune disease, amiodarone/lithium/checkpoint-inhibitor therapy, pregnancy with risk factors, neonatal screening

TPO antibody - Hashimoto's (80-99%), also 70-80% of Graves'; predicts progression of subclinical hypothyroidism (~4%/year if positive)
TRAb - Graves' (70-100%); crosses the placenta - measure in the second trimester in any woman with current or past Graves'
Autoimmune clustering: T1DM, coeliac, Addison's, pernicious anaemia, vitiligo
Down and Turner syndromes
Post-partum thyroiditis (~5-10% of women; higher if TPO positive)

Subclinical hypothyroidism: progression to overt disease ~2-4%/year, higher with TSH >10 or positive TPO
Many mildly abnormal TFTs normalise on repeat - confirm before treating
Levothyroxine over-replacement (suppressed TSH) -> AF and osteoporosis, particularly in older women
The commonest reason for a persistently raised TSH on adequate levothyroxine is adherence or absorption, not dose
- Missed doses then catch-up before the visit -> high fT4 with a still-high TSH

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