Thyroid function tests, Graves disease, thyroid eye disease, hypothyroidism and thyroid nodules

Overview

Thyroid disease is common, especially in women, and iodine deficiency goitre is still seen in the northern areas of Pakistan. Most MCQs can be answered by reading the TSH and FT4 (unbound thyroxine) pattern correctly, knowing the causes of thyrotoxicosis and their uptake scans, and knowing the treatment rules and drug side effects for Graves disease and hypothyroidism.

Thyroid function tests

• The hypothalamus releases TRH, the pituitary TSH, and the thyroid mainly T4 (converted to the more active T3 in tissues). T4 and T3 feed back to suppress TSH.
• TSH is the most sensitive test of primary thyroid disease, because small changes in T4 cause large changes in TSH.
• Measure FT4 (and FT3 if TSH is suppressed) rather than total T4, which rises with high thyroid-binding globulin (pregnancy, oral contraceptive pill).
• Typical adult ranges: TSH about 0.3–3.5 mU/L, FT4 about 10–25 pmol/L, FT3 about 3.5–7.5 pmol/L (labs differ).

Patterns

Other tests

• TPO antibodies: autoimmune thyroiditis (Hashimoto, atrophic); also found in up to 20% of normal women.
• TSH receptor antibodies (TRAb): specific for Graves disease (modern assays about 97–99% specific); high levels predict relapse.
• Thyroglobulin: cancer follow-up marker; low in factitious thyrotoxicosis.
• Uptake scan separates causes of thyrotoxicosis; ultrasound for nodules; calcitonin for medullary cancer.
• Drugs: amiodarone causes hypo- or hyperthyroidism, lithium goitre and hypothyroidism; monitor TFTs.

Thyrotoxicosis: causes and uptake

Graves disease

• Autoimmune: IgG antibodies stimulate the TSH receptor, causing hormone excess and goitre. Linked to HLA-B8/DR3 and other autoimmune diseases (vitiligo, pernicious anaemia, type 1 diabetes, myasthenia gravis).
• Commonest in women aged 20–40; relapsing and remitting course.

Clinical features

• Any thyrotoxicosis: weight loss despite good appetite, heat intolerance, sweating, tremor, palpitations, AF (especially elderly), anxiety, diarrhoea, oligomenorrhoea, proximal myopathy, warm moist skin, wide pulse pressure, lid retraction and lid lag.
• Only in Graves: thyroid eye disease (proptosis, chemosis, ophthalmoplegia), pretibial myxoedema, thyroid acropachy (clubbing, periosteal new bone).
• Elderly: apathetic thyrotoxicosis, AF or heart failure. Asian men: thyrotoxic periodic paralysis (weakness after a carbohydrate meal, low K+).

Treatment

Symptom control: propranolol (non-selective beta-blocker; also reduces T4 to T3 conversion). Avoid in asthma (use a rate-limiting calcium channel blocker).

Antithyroid drugs (thionamides): block thyroid peroxidase and hormone synthesis. Benefit appears after 2–3 weeks because T4 has a half-life of about 7 days.

• Titration regimen: start high, reduce every 4–6 weeks guided by FT4/FT3 (TSH may stay suppressed for months), continue for about 18 months, stop if euthyroid on a low dose.
• Block-and-replace: full-dose carbimazole plus levothyroxine; not used in pregnancy (carbimazole crosses the placenta more readily than T4).
• Relapse in about 50%, mostly within 2 years; relapse is more likely with large goitre, severe disease and high TRAb.

Radioactive iodine (131-I):

• Contraindicated in pregnancy and breastfeeding; avoid pregnancy for months afterwards.
• Can worsen thyroid eye disease (about 15% versus 3% with drugs), especially in smokers: avoid in active moderate–severe eye disease or give steroid cover.
• Most patients become hypothyroid over the following years: lifelong TFT monitoring.

Surgery (near-total or total thyroidectomy):

• For large goitre with pressure symptoms, suspected cancer, drug failure in pregnancy (second trimester), patient choice, or active eye disease where radioiodine is unwise.
• Make the patient euthyroid first; potassium iodide for about 10 days before surgery reduces gland vascularity (Wolff–Chaikoff effect).
• Complications: neck haematoma with airway compression (open the wound at the bedside), recurrent laryngeal nerve palsy (about 1%), hypocalcaemia (transient in up to 10%, permanent below 1%), hypothyroidism.

Thyroid storm (crisis)

• Life-threatening flare (mortality about 10%): hyperpyrexia, severe tachycardia or AF, heart failure, agitation, delirium, vomiting, jaundice.
• Triggers: infection, surgery or radioiodine in an unprepared patient, stopping drugs, childbirth.
• Treat: propranolol, PTU (or carbimazole) in high dose, then iodide (given at least an hour after the thionamide), hydrocortisone, IV fluids, cooling (paracetamol, not aspirin), treat the trigger, ICU care.

Graves disease in pregnancy

• PTU in the first trimester, switch to carbimazole in the second and third trimesters; lowest effective dose; no block-and-replace; no radioiodine.
• Maternal TRAb crosses the placenta and can cause fetal and neonatal thyrotoxicosis, even after the mother has been cured by surgery or radioiodine. Fetal heart rate above 160/min is a warning sign.

Thyroid eye disease (Graves orbitopathy)

• An autoimmune inflammation of orbital fat and extraocular muscles (orbital fibroblasts carry TSH receptors). Glycosaminoglycan (hyaluronan) deposition draws in water, swelling the muscle bellies while sparing the tendons; later fibrosis.
• Can occur when the patient is hyper-, eu- or hypothyroid. Smoking makes it more common and more severe.

Features

• Gritty, watery eyes; lid retraction, lid lag, proptosis (usually bilateral, can be one-sided), periorbital and conjunctival oedema (chemosis).
• Diplopia: the inferior rectus is most often involved (restricted upgaze), then the medial rectus.
• Exposure keratopathy when lids cannot close.
• Optic neuropathy (compression at the orbital apex): loss of acuity and colour vision, field defect, afferent pupil defect. Sight-threatening.

Assessment

• Thyroid function and TRAb; CT or MRI of the orbits (enlarged muscles, crowded apex) when the diagnosis or optic nerve is in doubt; visual acuity, colour vision and fields.

Management (joint endocrine and eye care)

• Stop smoking; restore euthyroidism and avoid hypothyroidism (which worsens the eyes).
• Mild: lubricating drops (hypromellose), sleeping head-up, taping lids at night, selenium.
• Active moderate–severe: IV methylprednisolone pulses (or oral steroids); orbital radiotherapy; other immunosuppressants.
• Optic neuropathy: urgent IV steroids, then orbital decompression if no rapid response.
• Inactive disease (stable for about 6 months): rehabilitative surgery in order: decompression, then squint surgery, then eyelid surgery.

Hypothyroidism

Causes

• Primary (most cases): autoimmune (atrophic thyroiditis; Hashimoto thyroiditis with a firm rubbery goitre and high TPO antibodies); after radioiodine or thyroidectomy; iodine deficiency (endemic goitre); drugs (lithium, amiodarone, antithyroid drugs, interferon); postpartum and subacute thyroiditis (often temporary); congenital (agenesis, dyshormonogenesis, Pendred syndrome with deafness).
• Secondary: pituitary or hypothalamic disease.

Clinical features

• Tiredness, weight gain, cold intolerance, constipation, dry skin, hair loss, hoarse voice, slow thinking, depression, menorrhagia or amenorrhoea, carpal tunnel syndrome.
• Bradycardia, slow-relaxing reflexes, puffy face, non-pitting oedema (myxoedema), pericardial effusion, goitre in some.
• Children: slow growth, delayed puberty, poor school performance.
• Associated findings: raised cholesterol, raised CK, hyponatraemia, anaemia (normocytic; macrocytic if pernicious anaemia coexists), raised prolactin.

Diagnosis

• High TSH with low FT4. TPO antibodies confirm autoimmune cause.
• Check TFTs in anyone with unexplained tiredness, amenorrhoea, infertility, hyperprolactinaemia, dementia, hyponatraemia or high cholesterol.
• Congenital hypothyroidism (about 1 in 3500 births) is detected by the neonatal heel-prick TSH; early treatment prevents intellectual disability.

Treatment: levothyroxine for life

• Young, fit adults: about 100 µg daily (or about 1.6 µg/kg).
• Elderly or frail: 50 µg daily, increasing slowly.
• Ischaemic heart disease: 25 µg daily, increase every 3–4 weeks while watching for angina.
• Separate from iron, calcium and PPIs; think of coeliac disease if needs keep rising.
• Check TSH 6–8 weeks after each dose change; adjust by 25–50 µg; aim for TSH in the lower part of the normal range. Usual maintenance 100–150 µg daily.
• Avoid TSH suppression: risk of AF and osteoporosis.
• Pregnancy: increase dose by about 25–50 µg as soon as pregnancy is confirmed; untreated maternal hypothyroidism harms the child's development.

Subclinical hypothyroidism

• Raised TSH with normal FT4. Repeat in 3–6 months (many normalise).
• Treat when repeated TSH values exceed 10 mU/L, or if there are symptoms, TPO antibodies, goitre, or the woman is pregnant or planning pregnancy.

Myxoedema coma

• Rare emergency in the elderly: hypothermia, confusion or coma, bradycardia, hypoventilation, hypoglycaemia, hyponatraemia, heart failure; often triggered by infection or cold.
• ICU care; IV or oral T3 (liothyronine) in small doses (or IV T4); hydrocortisone 100 mg IV 8-hourly (until adrenal failure is excluded); slow passive rewarming; glucose; ventilation if needed.

Thyroid nodules and goitre

• About 5% of solitary or dominant nodules are malignant.
• Red flags: rapid growth, hard fixed nodule, hoarseness (recurrent laryngeal nerve), stridor, cervical lymph nodes, childhood neck irradiation, family history of thyroid cancer or MEN 2, extremes of age, male sex.

Step-by-step evaluation

1. TSH first.
   • Low TSH: do an uptake scan. A hot (functioning) nodule is almost never malignant; treat the thyrotoxicosis (radioiodine or surgery). No FNA needed.
   • Normal or high TSH: go to ultrasound.
2. Ultrasound: suspicious features are solid hypoechoic nodule, microcalcifications, irregular margins, taller-than-wide shape, extra-thyroid spread and abnormal nodes. Pure cysts are low risk.
3. Ultrasound-guided FNA cytology of suspicious or large nodules. Reported in graded categories from benign to malignant. FNA has about a 5% false-negative rate, so benign nodules are followed up.
4. Cold nodule on scan: about 10% malignant (FNA has largely replaced scans for this).
5. Surgery for malignant or suspicious cytology, indeterminate (follicular) lesions, pressure symptoms or cosmetic concern.

Thyroid cancers

• Differentiated (papillary, follicular): total or near-total thyroidectomy, radioiodine ablation, TSH-suppressive levothyroxine, follow-up with serum thyroglobulin (and neck ultrasound). Anti-thyroglobulin antibodies make the test unreliable.

Other thyroiditis to recognise

• De Quervain (subacute granulomatous): painful tender gland after a viral illness, high ESR, low uptake; thyrotoxic then hypothyroid phase. Treat with NSAIDs or aspirin, prednisolone if severe, beta-blocker. Antithyroid drugs do not help.
• Postpartum thyroiditis: painless; may be mistaken for postnatal depression; check TFTs.
• Riedel thyroiditis: woody hard gland with fibrosis spreading into neck tissues; an IgG4-related disease; mimics anaplastic cancer.

Quick revision

• TSH first; high TSH + low FT4 = primary hypothyroidism; low FT4 + low/normal TSH = pituitary.
• TRAb = Graves; TPO = Hashimoto; low thyroglobulin = factitious thyrotoxicosis.
• Diffuse high uptake = Graves; very low uptake = thyroiditis, iodine, factitious.
• Carbimazole 18 months; sore throat → stop and FBC; PTU in first trimester and storm.
• Radioiodine: not in pregnancy or breastfeeding; may worsen eye disease.
• Eye disease: smokers, inferior rectus, colour vision loss = optic neuropathy → IV steroids/decompression.
• Levothyroxine 100 µg young, 50 µg elderly, 25 µg IHD; TSH at 6–8 weeks; steroids first if hypopituitary.
• Subclinical hypothyroidism: treat if TSH >10, pregnancy or symptoms.
• Nodule: TSH → ultrasound → FNA; hot nodule rarely malignant; FNA cannot diagnose follicular cancer.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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